Process for the synthesis of E1 activating enzyme inhibitors

ABSTRACT

The present invention provides processes and synthetic intermediate (Ia) for the synthesis of 4-substituted ((1S, 2S, 4R)-2-hydroxy-4-{7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamates. These sulfamate compounds are E1 activating enzyme inhibitors, and are useful for the treatment of disorders of cell proliferation, particularly cancer, and other disorders associated with E1 activity.

PRIORITY CLAIM

This application claims priority from U.S. Provisional PatentApplication Ser. No. 60/963,008, filed Aug. 2, 2007, and U.S.Provisional Patent Application Ser. No. 61/062,378, filed Jan. 25, 2008,both which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to processes for the synthesis of E1activating enzyme inhibitors and intermediates useful in such processes.

BACKGROUND OF THE INVENTION

The post-translational modification of proteins by ubiquitin-likemolecules (ubls) is an important regulatory process within cells,playing key roles in controlling many biological processes includingcell division, cell signaling and the immune response. Ubls are smallproteins that are covalently attached to a lysine on a target proteinvia an isopeptide linkage with a C-terminal glycine of the ubl. Theubiquitin-like molecule alters the molecular surface of the targetprotein and can affect such properties as protein-protein interactions,enzymatic activity, stability and cellular localization of the target.

Ubiquitin and other ubls are activated by a specific E1 enzyme whichcatalyzes the formation of an acyl-adenylate intermediate with theC-terminal glycine of the ubl. The activated ubl molecule is thentransferred to the catalytic cysteine residue within the E1 enzymethrough formation of a thioester bond intermediate. The E1-ublintermediate and an E2 associate, resulting in a thioester exchangewherein the ubl is transferred to the active site cysteine of the E2.The ubl is then conjugated to the target protein, either directly or inconjunction with an E3 ligase, through isopeptide bond formation withthe amino group of a lysine side chain in the target protein.

Targeting E1 activating enzymes provides a unique opportunity tointerfere with a variety of biochemical pathways important formaintaining the integrity of cell division and cell signaling. E1activating enzymes function at the first step of ubl conjugationpathways; thus, inhibition of an E1 activating enzyme will specificallymodulate the downstream biological consequences of the ubl modification.As such, inhibition of these activating enzymes, and the resultantinhibition of downstream effects of ubl-conjugation, represents a methodof interfering with the integrity of cell division, cell signaling, andseveral aspects of cellular physiology which are important for diseasemechanisms. Thus, E1 enzymes such as UAE, NAE, and SAE, as regulators ofdiverse cellular functions, are potentially important therapeutictargets for the identification of novel approaches to treatment ofdiseases and disorders.

Langston S. et al. U.S. patent application Ser. No. 11/700,614, which ishereby incorporated by reference in its entirety, discloses compoundswhich are effective inhibitors of E1 activating enzymes, particularlyNAE. The compounds are useful for inhibiting E1 activity in vitro and invivo and are useful for the treatment of disorders of cellproliferation, particularly cancer, and other disorders associated withE1 activity. One class of compounds described in Langston et al. are4-substituted ((1S, 2S,4R)-2-hydroxy-4-{7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamates. Efficient chemical synthesis of these compounds can bechallenging due to the multiple stereogenic centers in these compounds.There is, thus, a need for additional processes for the preparation of4-substituted ((1S, 2S,4R)-2-hydroxy-4-{7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamates.

DESCRIPTION OF THE INVENTION

The present invention provides processes and intermediates for thesynthesis of 4-substituted ((1S, 2S,4R)-2-hydroxy-4-{7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methylsulfamates, which are useful as E1 activating enzyme inhibitors.

In one aspect the invention relates to a process for the synthesis of acompound of formula (I):

or a salt thereof; wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   R^(a) is hydrogen or a hydroxyl protecting group; or R^(a) taken        together with R^(j) and the intervening atoms forms a cyclic        diol protecting group; or R^(a) taken together with R^(m) and        the intervening atoms forms a cyclic diol protecting group;    -   R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally        substituted C₁₋₄ aliphatic;    -   R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(e) is hydrogen or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic;    -   R^(g) is chloro, fluoro, iodo or bromo;    -   R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) taken        together with R^(a) and the intervening atoms forms a cyclic        diol protecting group;    -   R^(k) is hydrogen or C₁₋₄ aliphatic;    -   R^(m) is a hydroxyl protecting group; or R^(m) taken together        with R^(a) and the intervening atoms forms a cyclic diol        protecting group;    -   said process comprising the step of combining a compound of        formula (II), or a salt thereof, with a compound of formula (II)        to afford a compound of formula (I);

wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(g), R^(h), R^(h′), R^(j), R^(k), and R^(m) in        formulas (II) and (III) is as defined in formula (I);    -   R^(l) is —CH₂CHO or —CH₂CH(OR^(l′))₂; and    -   each R^(l′) is independently C₁₋₆ aliphatic, or two R^(l′) are        taken together with the intervening oxygen and carbon atoms to        form an optionally substituted 5- or 6-membered cyclic acetal        moiety.

In some embodiments, the process further comprises the step:

-   -   c) treating the compound of formula (I) with an amine of formula        HNR^(n)R^(o) to form a compound of formula (V), or a salt        thereof;

wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(h), R^(h′), R^(j), R^(k), and R^(m) in formula (V) is        as defined in formula (I);    -   R^(n) is H or C₁₋₄ aliphatic; and    -   R^(o) is optionally substituted C₁₋₁₀ aliphatic, aryl,        heteroaryl or heterocyclic.

In some embodiments, the process further comprises the step:

-   -   d) sulfamoylating a compound of formula (V), wherein R^(j) is        hydrogen to form a compound of formula (VI), or a salt thereof;

wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(h), R^(h′), R^(k), R^(m), R^(n), and R^(o) in        formula (VI) is as defined in formula (V).

Another aspect of the invention relates to another process for forming acompound of formula (I):

or a salt thereof; wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   R^(a) is hydrogen or a protecting group; or R^(a) taken together        with R^(j) and the intervening atoms forms a cyclic diol        protecting group; or R^(a) taken together with R^(m) and the        intervening atoms forms a cyclic diol protecting group;    -   R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally        substituted C₁₋₄ aliphatic;    -   R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(e) is hydrogen or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic;    -   R^(g) is chloro, fluoro, iodo or bromo;    -   R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(j) is hydrogen or a protecting group; or R^(j) taken together        with R^(a) and the intervening atoms forms a cyclic diol        protecting group;    -   R^(k) is hydrogen or C₁₋₄ aliphatic;    -   R^(m) is a hydroxyl protecting group; or R^(m) taken together        with R^(a) and the intervening atoms forms a cyclic diol        protecting group;    -   said process comprising treating a compound of formula (IV):

-   -   with an acid to form the compound of formula (I), wherein:    -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(h), R^(h′), R^(j), R^(k), and R^(m) in formula (IV) is        as defined in formula (I);    -   R^(l) is —CH₂CH(OR^(l′))₂; and    -   each R^(l′) is independently C₁₋₆ aliphatic, or two R^(l′) are        taken together with the intervening oxygen and carbon atoms to        form an optionally substituted 5- or 6-membered cyclic acetal        moiety.

Another aspect of the invention relates to a process for forming acompound of formula (V):

or a salt thereof; wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate relative stereochemistry;    -   R^(a) is hydrogen or a protecting group; or R^(a) taken together        with R^(j) and the intervening atoms forms a cyclic diol        protecting group; or R^(a) taken together with R^(m) and the        intervening atoms forms a cyclic diol protecting group;    -   R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally        substituted C₁₋₄ aliphatic;    -   R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(e) is hydrogen or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic;    -   R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) taken        together with R^(a) and the intervening atoms forms a cyclic        diol protecting group;    -   R^(k) is hydrogen or C₁₋₄ aliphatic;    -   R^(m) is a hydroxyl protecting group; or R^(m) taken together        with R^(a) and the intervening atoms forms a cyclic diol        protecting group.    -   R^(n) is H or C₁₋₄ aliphatic;    -   R^(o) is optionally substituted C₁₋₁₀ aliphatic, aryl,        heteroaryl or heterocyclic;    -   said process comprising treating a compound of formula (Ia):

-   -   with an amine of formula HNR^(n)R^(o), wherein:    -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(h), R^(h′), R^(j), R^(k), and R^(m) in formula (Ia) is        as defined in formula (V); and    -   R^(g′) is a leaving group.

Another aspect of the invention relates to compounds of formula (Ia):

or a salt thereof; wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate absolute stereochemistry;    -   R^(a) is hydrogen or a protecting group; or R^(a) taken together        with R^(j) and the intervening atoms forms a cyclic diol        protecting group; or R^(a) taken together with R^(m) and the        intervening atoms forms a cyclic diol protecting group;    -   R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally        substituted C₁₋₄ aliphatic;    -   R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(e) is hydrogen or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic;    -   R^(g′) is a leaving group;    -   R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) taken        together with R^(a) and the intervening atoms forms a cyclic        diol protecting group;    -   R^(k) is hydrogen or C₁₋₄ aliphatic; and    -   R^(m) is a hydroxyl protecting group; or R^(m) taken together        with R^(a) and the intervening atoms forms a cyclic diol        protecting group.

Another aspect of this invention relates to compounds of formula (IIa):

or a salt thereof; wherein:

-   -   stereochemical configurations depicted at asterisk positions        indicate absolute stereochemistry;    -   R^(a) is hydrogen or a protecting group; or R^(a) taken together        with R^(j) and the intervening atoms forms a cyclic diol        protecting group; or R^(a) taken together with R^(m) and the        intervening atoms forms a cyclic diol protecting group;    -   R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally        substituted C₁₋₄ aliphatic;    -   R^(d′) is hydrogen, fluoro, bromo, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(e) is hydrogen or C₁₋₄ aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic;    -   R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic;    -   R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) taken        together with R^(a) and the intervening atoms forms a cyclic        diol protecting group;    -   R^(m) is a hydroxyl protecting group; or R^(m) taken together        with R^(a) and the intervening carbon atoms forms a cyclic diol        protecting group; and    -   R^(r) is hydrogen or an amine protecting group.

Compounds and processes of this invention include those describedgenerally above, and are further illustrated by the detaileddescriptions of processes and compounds given below. Terms used hereinshall be accorded the following defined meanings, unless otherwiseindicated.

As used herein, the term “E1,” “E1 enzyme,” or “E1 activating enzyme”refers to any one of a family of related ATP-dependent activatingenzymes involved in activating or promoting ubiquitin or ubiquitin-like(collectively “ubl”) conjugation to target molecules. E1 activatingenzymes function through an adenylation/thioester intermediate formationto transfer the appropriate ubl to the respective E2 conjugating enzymethrough a transthiolation reaction. The resulting activated ubl-E2promotes ultimate conjugation of the ubl to a target protein. A varietyof cellular proteins that play a role in cell signaling, cell cycle, andprotein turnover are substrates for ubl conjugation which is regulatedthrough E1 activating enzymes (e.g., NAE, UAE, SAE). Unless otherwiseindicated by context, the term “E1 enzyme” is meant to refer to any E1activating enzyme protein, including, without limitation, nedd8activating enzyme (NAE (APPBP1/Uba3)), ubiquitin activating enzyme (UAE(Uba1)), sumo activating enzyme (SAE (Aos1/Uba2)), or ISG15 activatingenzyme (Ube1L), preferably human NAE, SAE or UAE, and more preferablyNAE.

The term “E1 enzyme inhibitor” or “inhibitor of E1 enzyme” is used tosignify a compound having a structure as defined herein, which iscapable of interacting with an E1 enzyme and inhibiting its enzymaticactivity. Inhibiting E1 enzymatic activity means reducing the ability ofan E1 enzyme to activate ubiquitin like (ubl) conjugation to a substratepeptide or protein (e.g., ubiquitination, neddylation, sumoylation).

The term “aliphatic” or “aliphatic group”, as used herein, means asubstituted or unsubstituted straight-chain, branched or cyclic C₁₋₁₂hydrocarbon, which is completely saturated or which contains one or moreunits of unsaturation, but which is not aromatic. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Invarious embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to 6, 1to 4, or 1 to 3 carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from 1 to 12 carbon atoms. For purposes of the present invention,the term “alkyl” will be used when the carbon atom attaching thealiphatic group to the rest of the molecule is a saturated carbon atom.However, an alkyl group may include unsaturation at other carbon atoms.Thus, alkyl groups include, without limitation, methyl, ethyl, propyl,allyl, propargyl, butyl, pentyl, and hexyl.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on the cycloaliphaticring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring. The term “cycloaliphatic” may be used interchangeablywith the terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic”.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on the arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,C₆₋₁₀ aryl(C₁₋₄)alkyl, or C₆₋₁₀ aryl(C₁₋₃)alkyl, including, withoutlimitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. In some embodiments, twoadjacent substituents on the heteroaryl, taken together with theintervening ring atoms, form an optionally substituted fused 5- to6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of O, N, and S.Thus, the terms “heteroaryl” and “heteroar-”, as used herein, alsoinclude groups in which a heteroaromatic ring is fused to one or morearyl, cycloaliphatic, or heterocyclyl rings, where the radical or pointof attachment is on the heteroaromatic ring. Nonlimiting examplesinclude indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-,bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”, any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclic”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro. Nonlimiting examples of fluoroaliphatics include —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CF₂CH₃, and —CF₂CF₃.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms is replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group. An alkylene chain also may be substitutedat one or more positions with an aliphatic group or a substitutedaliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R*)═C(R*)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R*)—, —N(R⁺)CO—,—N(R⁺)C(O)N(R⁺)—, —N(R⁺)CO₂—, —C(O)N(R⁺)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —OC(O)N(R⁺)—, —C(NR⁺)═N, —C(OR*)═N—, —N(R⁺)—N(R⁺)—,or —N(R⁺)S(O)₂—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a 5-8 membered aromatic or non-aromatic ring having, in addition tothe nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S. EachR* independently is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include —CH₂OCH₂—, —CH₂O(CH₂)₂—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—,—(CH₂)₂OCH₂—, —(CH₂)₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—, —(CH₂)₃O(CH₂)—,—(CH₂)₃O(CH₂)₂—, and —(CH₂)₄O(CH₂)—. Other examples of alkylene chainsthat are “interrupted” with functional groups include —CH₂ZCH₂—,—CH₂Z(CH₂)₂—, —CH₂Z(CH₂)₃—, —CH₂Z(CH₂)₄—, —(CH₂)₂ZCH₂—, —(CH₂)₂Z(CH₂)₂—,—(CH₂)₂Z(CH₂)₃—, —(CH₂)₃Z(CH₂)—, —(CH₂)₃Z(CH₂)₂—, and —(CH₂)₄Z(CH₂)—,wherein Z is one of the “interrupting” functional groups listed above.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention. A stable or chemically feasible compound is one inwhich the chemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., in the absence ofmoisture or other chemically reactive conditions, for at least a week,or a compound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The phrase “one or more substituents”, asused herein, refers to a number of substituents that equals from one tothe maximum number of substituents possible based on the number ofavailable bonding sites, provided that the above conditions of stabilityand chemical feasibility are met. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and the substituents may be eitherthe same or different.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(oo), —S(O)R^(oo), —SO₂R^(oo),—SO₃R^(oo), —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂,—NR⁺CO₂R^(oo), —O—CO₂R*, —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*,—C(O)R*, —C(O)N(R⁺)₂, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*,—N(R⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —NR⁺SO₂R^(oo), —NR⁺SO₂N(R⁺)₂,—P(O)(R*)₂, —P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂, whereinR^(oo) is an optionally substituted aliphatic or aryl group, and R⁺ andR* are as defined above, or two adjacent substituents, taken togetherwith their intervening atoms, form a 5-6 membered unsaturated orpartially unsaturated ring having 0-3 ring atoms selected from the groupconsisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing; ═O, ═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(oo), ═N—NHSO₂R^(oo), or ═N—R*, where each R* and R^(oo) is asdefined above.

Suitable substituents on the nitrogen atom of a non-aromaticheterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R*,—C(O)—C(O)R*—C(O)CH₂C(O)R*, —SO₂R*, —SO₂N(R*)₂, —C(═S)N(R*)₂,—C(═NH)—N(R*)₂, and —NR*SO₂R*; wherein each R* is as defined above.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

As used herein, the term “comprises” means “includes, but is not limitedto”.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructure except for the replacement of a hydrogen atom by a deuteriumor tritium, or the replacement of a carbon atom by a ¹³C- or¹⁴C-enriched carbon are within the scope of the invention.

It also will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention. Unless stereochemical configuration is expressly defined,structures depicted herein are meant to include all stereochemical formsof the structure; i.e., the R and S configurations for each asymmetriccenter. Therefore, unless otherwise indicated, single stereochemicalisomers as well as enantiomeric and diastereomeric mixtures of thepresent compounds are within the scope of the invention. By way ofexample, the compounds of formula (VI) wherein R^(c) is —OH can have Ror S configuration at the carbon atom bearing R^(c). Both the R and theS stereochemical isomers, as well as all mixtures thereof, are includedwithin the scope of the invention.

Where stereochemical configuration at a given asymmetric center isdefined by structure, unless stated otherwise, the depictedconfiguration indicates stereochemistry relative to other asymmetriccenters in the molecule. Where stereochemical configuration is definedby chemical name, the designations (rel), (R*), and (S*) indicaterelative stereochemistry, while the designations (R), (S), (+), (−), and(abs) indicate absolute stereochemistry.

In the compounds of formula (I)-(VI), stereochemical configurationsdepicted at asterisked positions indicate relative stereochemistry,unless expressly stated to indicate absolute stereochemistry.Preferably, the diastereomeric purity of the compound is at least 80%,more preferably at least 90%, still more preferably at least 95%, andmost preferably at least 99%. As used herein, the term “diastereomericpurity” refers to the amount of a compound having the depicted relativestereochemistry, expressed as a percentage of the total amount of alldiastereomers present.

In some embodiments, stereochemical configurations depicted atasterisked positions indicate absolute as well as relativestereochemistry. Preferably, the enantiomeric purity of the compound isat least 80%, more preferably at least 90%, still more preferably atleast 95%, and most preferably at least 99%. As used herein, the term“enantiomeric purity” refers to the amount of a compound having thedepicted absolute stereochemistry, expressed as a percentage of thetotal amount of the depicted compound and its enantiomer.

Methods for determining diastereomeric and enantiomeric purity arewell-known in the art. Diastereomeric purity can be determined by anyanalytical method capable of quantitatively distinguishing between acompound and its diastereomers. Examples of suitable analytical methodsinclude, without limitation, nuclear magnetic resonance spectroscopy(NMR), gas chromatography (GC), and high performance liquidchromatography (HPLC). Similarly, enantiomeric purity can be determinedby any analytical method capable of quantitatively distinguishingbetween a compound and its enantiomer. Examples of suitable analyticalmethods include, without limitation, GC or HPLC using a chiral columnpacking material. Enantiomers may also be distinguishable by GC or HPLCusing an achiral column packing material if first derivatized with anoptically enriched derivatizing agent, e.g., Mosher's acid. Similarly,enantiomers may also be distinguishable by NMR if first derivatized withan optically enriched derivatizing agent.

As used herein, the term “hydroxyl protecting group” refers to achemical group that: i) reacts with a hydroxyl functional group of asubstrate to form a protected substrate; ii) is stable to reactionconditions to which the protected substrate will be subjected; and iii)is removable from a protected substrate to liberate the hydroxylfunctional group under conditions that are compatible with otherfunctionality present in the substrate. As used herein, the term “cyclicdiol protecting group” refers to a chemical group that: i) reacts with adiol functional group of a substrate to form a protected substrate; ii)is stable to reaction conditions to which the protected substrate willbe subjected; and iii) is removable from a protected substrate toliberate the diol functional group under conditions that are compatiblewith other functionality present in the substrate. The hydroxyl groupsof 1,2- and 1,3-diols may be individually protected with hydroxylprotecting groups or may be jointly protected with a cyclic diolprotecting group.

As used herein the term “acid labile protecting group” refers to achemical group that: i) reacts with a functional group of substrate toform a protected substrate; ii) is stable to reaction conditions towhich the protected substrate will be subjected, and iii) is removablefrom a protected substrate to liberate the functional group under acidicconditions that are compatible with other functionality present in thesubstrate. Amine and hydroxyl groups are among the functional groupsthat may be protected with an acid-labile protecting group.

As used herein the term “amine protecting group” refers to a chemicalgroup that: i) reacts with an amine functional group of a substrate toform a protected substrate; ii) is stable to reaction conditions towhich the protected substrate will be subjected; and iii) is removablefrom a protected substrate to liberate the amine under conditions thatare compatible with other functionality present in the substrate.

Hydroxyl protecting groups, cyclic diol protecting groups, acid-labileprotecting groups and amine protecting groups that are suitable for usein the processes and compounds of the present invention are known tothose of ordinary skill in the art. The chemical properties of suchprotecting groups, methods for their introduction and their removal canbe found, for example, in P. G. M. Wuts and T. W. Greene, Greene'sProtective Groups in Organic Synthesis (4^(th)ed.), John Wiley & Sons,NJ (2007).

The processes and compounds of the present invention are furtherillustrated by the detailed descriptions and illustrative examples givenbelow.

In a first aspect, the invention relates to a process for forming acompound of formula (I) by combining a compound of formula (II) with acompound of formula (III). In one embodiment, wherein R^(l) is—CH₂CH(OR^(l′))₂, and each R^(l′) is independently C₁₋₆ aliphatic, ortwo R^(l′) are taken together with the intervening oxygen and carbonatoms to form an optionally substituted 5- or 6-membered cyclic acetalmoiety, the process comprises the steps:

-   -   a) treating a compound of formula (II), or a salt thereof, with        a compound of formula (III) in the presence of a base to afford        a compound of formula (IV); and    -   b) treating a reaction mixture comprising the compound of        formula (IV) with an acid to form the compound of formula (I).

Step a) involves a nucleophilic displacement reaction between a compoundof formula (II) and a compound of formula (III) to form compounds offormula (IV). Compounds of formula (IV) may be then converted tocompounds of formula (I) without isolation by the conditions of step b).Alternatively, compounds of formula (IV) can be isolated and/or purifiedby methods known to those of ordinary skill in the art and converted tocompounds of formula (I) in a separate reaction. (See J. A. Secrist etal. J. Med. Chem., 1984, 27, 534-536; R. B. Talekar and R. H. WightmanTetrahedron, 1997, 53, 3831-3842). Step b) involves treatment with anacid, leading to the acid-catalyzed removal of the acetal groups alongwith cyclization to form the 7H-pyrrolo[2,3-d]pyrimidin-7-yl ringsystem.

Step a) may be conveniently carried out in the presence of a base suchas an alkaline earth metal base or an organic amine base. Examples of analkaline earth metal base include, but are not limited to, potassiumcarbonate, sodium carbonate, calcium carbonate, lithium hydroxide,potassium hydroxide, sodium hydroxide, lithium hydrogen carbonate,potassium hydrogen carbonate, sodium hydrogen carbonate, lithiumhydride, potassium hydride, sodium hydride, lithium tert-butoxide,potassium tert-butoxide, and sodium tert-butoxide. Other alkaline earthmetal bases include, but are not limited to, cesium carbonate, andcesium hydroxide. Organic amine bases include, but are not limited to,trialkylamines, cyclic amines, pyridines and substituted pyridines.Examples of these include, but are not limited to, triethylamine,triethylenediamine, pyridine, collidine, 2,6-lutidine,4-dimethylaminopyridine, di-tertbutylpyridine, N-methylmorpholine,N-methylpiperidine, tetramethylguanidine, diazabicyclo[5.4.0]undec-7-ene(DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicycle[4.3.0]non-5-eneand N,N′diisopropylethylamine. Other organic amine bases include, butare not limited to, 1-azabicyclo[2.2.2]octane, tributylamine andtripropylamine. Preferably, the base used in step a) is selected frompotassium carbonate, potassium hydrogen carbonate, sodium carbonate,sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide,triethylamine, N,N′-diisopropylethylamine, pyridine, and 2,6-lutidine.

The treating of step a) may be performed at ambient or elevated reactiontemperature, though elevated temperatures may result in shorter reactiontimes. The selection of an appropriate reaction temperature and reactiontime will depend largely on the base and solvent used. One of ordinaryskill in the art will be able to select a suitable reaction temperatureand reaction time in view of the reaction conditions being used.

In some embodiments, step a) may be carried out at reaction temperaturesof at least about 20° C., 45° C. or 60° C. In some embodiments, step a)may be carried out at reaction temperatures no greater than 120° C.,105° C. or 90° C. Any ranges encompassing these high and lowtemperatures are included within the scope of the invention. Step a) ispreferably performed at reaction temperatures in the range of about 20°C. to about 120° C., about 45° C. to about 105° C., or about 60° C. toabout 90° C.

The acid used in step b) is a mineral acid or an organic acid. Examplesof mineral acids include, but are not limited to, hydrochloric acid,sulfuric acid, hydrobromic acid, nitric acid and phosphoric acid.Examples of organic acids include but are not limited to acetic acid,propionic acid, benzoic acid, formic acid, oxalic acid, trichloroaceticacid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acidand trifluoromethanesulfonic acid. Preferably, the acid in step b) isselected from the group consisting of hydrochloric acid, sulfuric acid,trifluoroacetic acid, p-toluenesulfonic acid, trichloroacetic acid,acetic acid, and formic acid.

The treating of step b) is preferably performed at ambient or elevatedreaction temperature, though elevated temperatures may result in shorterreaction times. The selection of an appropriate reaction temperature andreaction time will depend largely on the acid and solvent used. One ofordinary skill in the art will be able to select a suitable reactiontemperature and reaction time in view of the reaction conditions beingused.

In some embodiments, step b) may be carried out at reaction temperaturesof at least about 20° C., 40° C. or 50° C. In some embodiments, step b)may be carried out at reaction temperatures no greater than about 90°C., 70° C., 60° C. or 50° C. Any ranges encompassing these high and lowtemperatures are included within the scope of the invention. Step b) ispreferably performed at reaction temperatures in the range of about 20°C. to about 90° C., about 40° C. to about 60° C., or about 50° C. toabout 60° C. In some other embodiments, step b) is preferably performedat a reaction temperature in the range of about 45° C. to about 60° C.

In some embodiments, step a) and step b) independently are carried outin a solvent or diluent comprising one or more of ethanol, isopropanol,sec-butanol, ethyl acetate, methylene chloride, chloroform, carbontetrachloride, tetrahydrofuran, 2-methyltetrahydrofuran,dimethoxyethane, 1,4-dioxane, toluene, anisole, acetonitrile,N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, or mixtures thereof. In certain embodiments, each ofstep a) and step b) is carried out in a solvent comprising aqueousethanol, aqueous isopropanol, aqueous sec-butanol, aqueoustetrahydrofuran, aqueous 1,4-dioxane, or mixtures thereof. In someembodiments, each of step a) and step b) is carried out in a solventcomprising ethanol, isopropanol, sec-butanol, tetrahydrofuran or1,4-dioxane, or a mixture thereof.

In some embodiments, after the reaction is complete, the reactionmixture is allowed to cool to ambient temperature, concentrated and thenadded to an aqueous solution, following which the resulting product iscollected by filtration and dried. In some embodiments, the concentratedreaction mixture is added to water. In some other embodiments, theconcentrated reaction mixture is added to aqueous sodium chloridesolution. In yet some other embodiments, the concentrated reactionmixture is added to an aqueous basic solution to neutralize the acidintroduced in step b). Examples of aqueous basic solution include, butare not limited to, aqueous sodium carbonate, aqueous potassiumcarbonate and aqueous sodium bicarbonate.

Preferably, the process comprising steps a) and b) to form compounds offormula (I), wherein R^(l) is —CH₂CH(OR^(l′))₂ is characterized by atleast one of the following features:

-   -   (i) the base in step a) is triethylamine;    -   (ii) the treating of step a) is carried out in aqueous        isopropanol;    -   (iii) the treating of step b) is carried out in aqueous        isopropanol;    -   (iv) the acid in step b) is hydrochloric acid;    -   (v) the treating of step a) is performed at a reaction        temperature in the range of about 60° C. to about 90° C.; and    -   (vi) the treating of step b) is performed at a reaction        temperature in the range of about 40° C. to about 60° C.

In some embodiments, wherein R^(l) is —CH₂CH(OR^(l′))₂, the compounds offormula (IV) can be isolated and optionally purified by methods known tothose of ordinary skill in the art and converted to compounds of formula(I) in a separate reaction. In such embodiments, the conditions are asdescribed above for step b). Preferably, the process for forming thecompound of formula (I) from the compound of formula (IV), wherein R^(l)is —CH₂CH(OR^(l′))₂ is characterized by at least one of the followingfeatures:

-   -   (i) the treating is carried out in aqueous isopropanol;    -   (ii) the acid is hydrochloric acid; and    -   (iii) the treating is performed at a reaction temperature in the        range of about 50° C. to about 60° C.

In another embodiment, the process for forming a compound of formula (I)comprises treating a compound of formula (II) with a compound of formula(III), wherein R^(l) is —CH₂CHO, in the presence of a base. In thisembodiment, the combination of compounds of formula (II) and formula(II) to form a compound of formula (I) occurs in a single step, stepaa):

-   -   aa) treating a compound of formula (II), or a salt thereof, with        a compound of formula (II) in the presence of a base.

Suitable and preferred bases, solvents and reaction temperatures forstep aa) are as described above for step a).

Preferably, the process for forming a compound of formula (I) comprisingtreating a compound of formula (II) with a compound of formula (II),wherein R^(l) is —CH₂CHO, in the presence of a base is characterized byat least one of the following features:

-   -   (i) the base in step aa) is triethylamine;    -   (ii) the treating of step aa) is carried out in isopropanol; and    -   (iii) the treating of step aa) is performed at a reaction        temperature in the range of about 60° C. to about 90° C.

In some embodiments, after the reaction is complete, the reactionmixture is allowed to cool to ambient temperature, concentrated and thenadded to an aqueous solution, following which the resulting product iscollected by filtration and dried. In some embodiments, the concentratedreaction mixture is added to water. In some other embodiments, theconcentrated reaction mixture is added to aqueous sodium chloridesolution. In yet some other embodiments, the concentrated reactionmixture is added to an aqueous basic solution. Examples of aqueous basicsolution include, but are not limited to, aqueous sodium carbonate,aqueous potassium carbonate and aqueous sodium bicarbonate.

In some embodiments, the process described above further comprises thestep

-   -   c) treating the compound of formula (I) with an amine of formula        HNR^(n)R^(o) to form a compound of formula (V), or a salt        thereof.

In some embodiments, step c) may be conveniently carried out in thepresence of an acid or a base. In some embodiments, the base is analkaline earth metal base or an organic amine base. Examples of suchbases are described above for step a). Preferably the base in step c) isselected from potassium carbonate, potassium hydrogen carbonate, sodiumcarbonate, sodium hydrogen carbonate, sodium hydroxide, potassiumhydroxide, triethylamine, N,N′-diisopropylethylamine, pyridine and2,6-lutidine. The base can be used in equimolar amounts, in excess, or,if appropriate, as the solvent for the reaction.

In some embodiments the treating of step c) is carried out in a solventor diluent comprising one or more of ethanol, isopropanol, sec-butanol,n-butanol, ethyl acetate, methylene chloride, chloroform, carbontetrachloride, tetrahydrofuran, 2-methyltetrahydrofuran,dimethoxyethane, 1,4-dioxane, toluene, anisole, N,N′-dimethylformamide,N,N′-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide,diglyme, or mixtures thereof. In some embodiments, step c) may becarried out in water, or an aqueous solvent mixture comprising one ofmore of the solvents listed above. In some embodiments, step c) may becarried out without a solvent or diluent by employing an excess of theamine HNR^(n)R^(o). In some embodiments, the treating of step c) iscarried out in a solvent or diluent compromising one or more of toluene,anisole, N,N′-dimethylformamide, sec-butanol, diglyme, dimethylacetamideor N-methylpyrrolidinone.

The treating of step c) is preferably performed at ambient or elevatedreaction temperatures. In some embodiments, the treating of step c) isperformed under microwave irradiation conditions. The selection of anappropriate reaction temperature and reaction time will depend largelyon the base and solvent used. One skilled in the art will be able toselect a suitable reaction temperature and reaction time in view of thereaction conditions being used.

In some embodiments, step c) may be carried out at reaction temperaturesof at least about 50° C., 90° C. or 130° C. In some embodiments, step c)may be carried out at reaction temperatures no greater than about 160°C. or 145° C. Any ranges encompassing these high and low reactiontemperatures are included within the scope of the invention. Step c) ispreferably performed at reaction temperatures in the range of about 50°C. to about 160° C., about 90° C. to about 145° C., or about 130° C. toabout 145° C.

The treating of step c) may optionally be conducted under an elevatedreaction pressure. One skilled in the art will be able to select asuitable reaction pressure in view of the reaction conditions beingused. In some embodiments, step c) may be carried out at reactionpressures of at least about 50 psi or 70 psi. In some embodiments, stepc) may be carried out at reaction pressures no greater than about 120psi or 110 psi. Any ranges encompassing these high and low reactionpressures are included within the scope of the invention. If an elevatedreaction pressure is employed in step c), it is preferably performed atreaction pressures in the range of about 50 psi to about 120 psi, orabout 70 psi to about 110 psi. In some other embodiments, if an elevatedreaction pressure is employed in step c), it is preferably in the rangeof about 70 psi to about 100 psi.

In some embodiments, following the completion of step c), the reactionmixture is cooled to ambient temperature and pressure and extracted witha solvent such as ethyl acetate, isopropyl acetate, methyl ethyl ketone,methyl isobutyl ketone, toluene, or tert-butyl methyl ether. In someother embodiments, following the completion of step c), the reactionmixture is cooled to ambient temperature and pressure, concentrated andadded directly to water or a solvent such as ethyl acetate, methylenechloride, acetone, isopropyl acetate, methyl ethyl ketone, methylisobutyl ketone, toluene, tert-butyl methyl ether, diethyl ether oracetonitrile to effect product precipitation. The product is thencollected by filtration and dried.

Preferably, the process for forming a compound of formula (V) from acompound of formula (I) comprising step c) is characterized by at leastone of the following features:

-   -   (i) said base of step c) is N,N′-diisopropylethylamine;    -   (ii) the treating of step c) is carried out in sec-butanol;    -   (iii) the treating of step c) is performed at a reaction        temperature in the range of about 130° C. to about 145° C.; and    -   (iv) the treating of step c) is performed at a reaction pressure        in the range of about 70 psi to about 100 psi.

The invention also relates to a process for the formation of a compoundof formula (V) as defined above, comprising the treatment of a compoundof formula (Ia) as defined above with an amine of formula HNR^(n)R^(o).In some embodiments R^(g′) is halo, —O—R^(s), —S—R^(t), —S(O)R^(t) or—S(O)₂R^(t); wherein R^(s) is C₁₋₄ aliphatic, alkylsulphonyl,fluoroalkylsulphonyl, optionally substituted aryl or optionallysubstituted arylsulphonyl and R^(t) is optionally substituted C₁₋₄aliphatic or optionally substituted aryl.

Compounds of formula (Ia) wherein R^(g′) is —O—R^(s), —S—R^(t),—S(O)R^(t) or —S(O)₂R^(t) may be prepared from compounds of formula (I)by methods known to those of skill in the art. For example, R^(g) in acompound of formula (I) may be displaced with an alkoxide or a thiol togenerate compounds of formula (Ia) where R^(g′) is —O—R^(s), —S—R^(t),wherein R^(s) is optionally substituted C₁₋₄ aliphatic or optionallysubstituted aryl or R^(t) is optionally substituted C₁₋₄ aliphatic oroptionally substituted aryl. Compounds wherein R^(g′) is —S—R^(t) may befurther oxidized to generate compounds wherein R^(g′) is —S(O)R^(t) or—S(O)₂R^(t).

To generate compounds of formula (Ia), wherein R^(g′) is —O—R^(s) whenR^(s) is alkylsulfonyl, fluoroalkylsulphonyl or optionally substitutedarylsulphonyl, R^(g) in the compound of formula (I) must first beconverted to a hydroxyl group, followed by treatment with theappropriate sulfonylchloride or anhydride. Conversion of R^(g) to thehydroxyl group may be accomplished directly by treatment under basicconditions such as NaOH, or alternatively from a compound of formula(Ia) wherein R^(g′) is —OCH₃, which can be hydrolyzed to thecorresponding alcohol by treatment with aqueous NaOH ortrimethylsilylchloride/sodium iodide.

The displacement of R^(g′) in compounds of formula (Ia) withHNR^(n)R^(o) may be conveniently carried out in the presence of a basesuch as an alkaline earth metal base or an organic amine base. Examplesof suitable bases are described above for step c). The base can be usedin an equimolar amount, in excess, or, if appropriate, as the solventfor the reaction.

The displacement of R^(g′) in compounds of formula (Ia) withHNR^(n)R^(o) may be conveniently carried out in the presence of asuitable solvent or diluent. Examples of suitable solvents are describedabove for step c). In some embodiments the displacement of R^(g′) may becarried out without a solvent or diluent by employing an excess of theamine HNR^(n)R^(o).

The displacement of R^(g′) in compounds of formula (Ia) withHNR^(n)R^(o) is preferably performed at ambient or elevated reactiontemperatures. Suitable temperatures and ranges of temperatures are asdescribed above for step c).

The displacement of R^(g′) in compounds of formula (Ia) withHNR^(n)R^(o) may optionally be conducted under an elevated reactionpressure. Suitable pressures and ranges of pressures are as describedabove for step c).

In some embodiments the displacement of R^(g′) in compounds of formula(Ia) with HNR^(n)R^(o) may also be carried out in the presence of apalladium catalyst/ligand system. Suitable metal catalyst systems aresuch as those described in Prim D. et al. Tetrahedron, 2002, 58, 20412and Gunda P. et al. Angew. Chem. Intl. Ed., 2004, 43, 6372. Suitablebases include but are not limited to sodium tert-butoxide, cesiumcarbonate and K₃PO₄. Suitable solvents include but are not limited totoluene, 1,4-dioxane, tert-butanol and mixtures thereof.

In some embodiments when a palladium-catalyst/ligand system is employed,R^(g′) is chloride, bromide, iodide, triflate or —O—R^(s) where R^(s) isoptionally substituted arylsulfonyl. In certain such embodiments R^(g′)is chloride, bromide or triflate.

In some embodiments, the process of the invention further comprises thestep:

-   -   d) sulfamoylating a compound of formula (V), wherein R^(j) is        hydrogen, to form a compound of formula (VI), or a salt thereof;

wherein:

stereochemical configurations depicted at asterisk positions indicaterelative stereochemistry; and

-   -   each of variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),        R^(f), R^(h), R^(h′), R^(k), R^(m), R^(n), and R^(o) in        formula (VI) is as defined in formula (V).

Compounds of formula (VI), which are effective inhibitors of E1activating enzymes, particularly NAE, are disclosed in Langston S. etal. U.S. patent application Ser. No. 11/700,614, which is herebyincorporated by reference in its entirety, including all formulas, andall genus and sub-genus descriptions disclosed therein.

If R^(j) in a compound of formula (V) is other than hydrogen, i.e., ifR^(j) is a hydroxyl protecting group, it must be removed prior to theconversion to a compound of formula (VI). The deprotection step can beaccomplished by methods known to one of ordinary skill in the art.

In some embodiments, the sulfamoylating step d) comprises the steps:

-   -   I-A) treating a base in a solvent with a solution of        R^(u)NHS(O)₂Cl wherein R^(u) is hydrogen or an acid-labile        protecting group;    -   II-A) treating the reaction mixture formed in I-A) with the        compound of formula (V); and    -   III-A) optionally treating the reaction mixture formed in II-A)        with an acid.

Steps d) I-A), II-A) and III-A) may be conveniently carried out in thepresence of a suitable solvent or diluent, which may be the same ordifferent for each of steps d) I-A), II-A) and III-A). Examples ofsuitable solvents, include but are not limited to, ethyl acetate,methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, anisole,acetonitrile, N,N′-dimethylformamide, N,N′-dimethylacetamide,N-methylpyrrolidinone, dimethylsulfoxide, and mixtures thereof. In someembodiments, steps d) I-A), II-A) and III-A) are each carried out in asolvent comprising ethyl acetate, tetrahydrofuran,2-methyltetrahydrofuran, dimethoxyethane, acetonitrile,N,N′-dimethylacetamide, N-methylpyrrolidinone, DME, or mixtures thereof.

The base in step d) I-A) is an organic amine base. Examples of organicamine bases include, but are not limited to, trialkylamines, pyridineand substituted pyridines. Examples of these include but are not limitedto trimethylamine, triethylamine, triethylenediamine, pyridine,collidine, 2,6-lutidine, 4-dimethylaminopyridine,2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methylpyridine,1-azabicyclo[2.2.2]octane, tributylamine, tripropylamine,diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane,1,5-diazabicycle[4.3.0]non-5-ene, sparteine, andN,N′diisopropylethylamine.

In some embodiments in step d) I-A), R^(u)NHS(O)₂Cl is added to thesolvent at a rate sufficient to keep the temperature of the reactionbelow about 15° C.; and in step d) II-A), the reaction mixture iscooled, preferably to between about −10° C. and 0° C., and then thecompound of formula (V) is added neat or as a solution in a solvent. Inother embodiments, step d) I-A) is conducted at ambient temperature, andin step d) II-A), the reaction mixture is cooled, preferably to betweenabout −10° C. and 0° C., and then the compound of formula (V) is addedneat or as a solution in a solvent. In some embodiments, step d) I-A) isconducted at ambient temperature, and then the compound of formula (V)is added neat or as a solution in a solvent at ambient temperature instep d) II-A). In some embodiments, following the addition of thecompound of formula (V), the reaction mixture is allowed to warm toambient temperature.

In some other embodiments, the sulfamoylating step d) comprises thesteps:

-   -   I-B) treating the compound of formula (V) with a base;    -   II-B) treating the reaction mixture formed in step I-B) with a        solution of R^(u)NHS(O)₂Cl, wherein R^(u) is hydrogen or an        acid-labile protecting group; and    -   III-B) optionally treating the reaction mixture formed in step        III-B) with an acid.

Steps d) I-B), II-B) and III-B) may be conveniently carried out in thepresence of a suitable solvent or diluent, which may be the same ordifferent for each of steps d) I-B), II-B) and III-B). Examples ofsuitable solvents are as described above for steps d) I-A), II-A) andIII-A).

The base in step d) I-B), is a strong base. Examples of strong basesinclude, but are not limited to, n-butyl lithium, tert-butyl lithium,lithium diisopropylamide, potassium diisopropylamide, lithiumhexamethyldisilazane, potassium hexamethyldisilazane, sodiumhexamethyldisilazane and potassium tert-butoxide.

In compounds of formula R^(u)NHS(O)₂Cl, R^(u) is hydrogen or an amineprotecting group. In some embodiments, R^(u) is hydrogen. In otherembodiments, R^(u) is an acid-labile protecting group. In certainparticular embodiments, R^(u) is —C(O)N(Ph)₂. In other particularembodiments, R^(u) is —C(O)OC(R^(v))₂(R^(w)), wherein each R^(v) isindependently selected from optionally substituted C₁₋₁₀ aliphatic oroptionally substituted aryl, and R^(w) is optionally substituted C₁₋₁₀aliphatic or optionally substituted aryl. In some other particularembodiments, R^(u) is —C(O)OC(R^(v))₂(R^(w)), wherein each R^(v) isindependently selected from hydrogen or optionally substituted C₁₋₁₀aliphatic, and R^(w) is optionally substituted C₁₋₁₀ aliphatic oroptionally substituted aryl. In yet some other particular embodiments,R^(u) is —C(O)OC(R^(v))₂(R^(w)), wherein one R^(v) is optionallysubstituted C₁₋₁₀ aliphatic, and the other R^(v) is taken together withR^(w) to form an optionally substituted C₃₋₆ cycloaliphatic ring.

In some embodiments, R^(w) is methyl or phenyl. In some embodiments,each R^(v) independently is methyl, ethyl, butyl, hexyl, octyl orphenyl. In some other embodiments, each R^(v) independently is hydrogen,methyl or ethyl. In some other embodiments, one R^(v) taken togetherwith R^(w) is cyclopropyl, or cyclohexyl. In preferred embodiments,R^(u) is —C(O)OCMe₃, —C(O)OC(Me)₂Ph, —C(O)OC(Et)₂Ph or—C(O)OC(octyl)₂Ph. In other preferred embodiments, R^(u) is —C(O)OCH₂Phor —C(O)OCH(Me)Ph. In yet other preferred embodiments, R^(u) isC(O)OC(Me)₂Et,

In certain preferred embodiments, R^(u) is selected from the groupconsisting of —C(O)OCMe₃, —C(O)OCH₂Ph, —C(O)OCH(Me)Ph, C(O)OC(Me)₂Et,

In some other embodiments, the sulfamoylating step d) comprises thesteps:

-   -   I-C) treating the compound of formula (V) with a sulfamoylating        reagent R^(u)N⁻—S(O)₂X⁺ and an acid; and    -   II-C) optionally treating the reaction mixture formed in I-C)        with an acid; wherein R^(u) has the values and preferred values        as described above.

In compounds of formula R^(u)N⁻—S(O)₂X⁺, X is a tertiary amine or anitrogen-containing heteroaryl. In some embodiments, X is a tertiaryamine. Examples of suitable tertiary amines include, but are not limitedto, trimethylamine, triethylamine, triethylenediamine,diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane,1,5-diazabicycle[4.3.0]non-5-ene, sparteine, andN,N′diisopropylethylamine. Other examples of suitable tertiary aminesinclude, but are not limited to, tributylamine,1-azabicyclo[2.2.2]octane, N,N′-dimethylpiperazine, N-ethylmorpholine,and tripropylamine.

In some other embodiments, X is a nitrogen-containing heteroaryl.Examples of suitable nitrogen-containing heteroaryl include, but are notlimited to, unsubstituted or substituted pyridine, unsubstituted orsubstituted imidazole, and unsubstituted or substituted pyrrole.

In some other embodiments, X is a pyridine or a substituted pyridine.Examples of pyridines or substituted pyridines include, but are notlimited to, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine,2,6-di-tert-butylpyridine and 2,6-di-tert-butyl-4-methylpyridine.

In preferred embodiments, X is selected from the group consisting oftriethylamine, triethylenediamine, 1-azabicyclo[2.2.2]octane,N,N′-dimethylpiperazine, N-ethylmorpholine and pyridine. In certainpreferred embodiments, X is triethylenediamine.

Steps d) I-C) and II-C) may be conveniently carried out in the presenceof a suitable solvent or diluent. Examples of suitable solvents are asdescribed above for steps d) I-A), II-A) and III-A).

The acid used in step d) I-C) may be a mineral acid or an organic acid.Examples of mineral acids include but are not limited to hydrochloricacid, sulfuric acid, hydrobromic acid, nitric acid and phosphoric acid.Examples of organic acids include but are not limited to acetic acid,propionic acid, isobutyric acid, benzoic acid, formic acid, oxalic acid,trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid,p-toluensulfonic acid and trifluoromethanesulfonic acid.

In some embodiments, in step d) I-C) the treating is carried out at sucha rate to keep the reaction temperature below about 10° C. In someembodiments, in step d) I-C), the treating is carried out at ambienttemperature. In some other embodiments, in step d) I-C), the reactionmixture is treated with additional portions of the sulfamoylatingreagent and acid until the reaction is complete. In some suchembodiments, the treating with additional portions is carried out atroom temperature. In other such embodiments, the treating withadditional portions is carried out at reaction temperatures below about10° C.

In some embodiments, the sulfamoylating step d) comprises the steps:

-   -   I-D) treating the compound of formula (V) with a sulfamoylating        reagent R^(u)N⁻—S(O)₂X⁺; and    -   II-D) optionally treating the reaction mixture formed in step d)        I-D) with an acid;    -   wherein R^(u) and X have the values and preferred values as        described above.

In some embodiments, the treating of step d) I-D) occurs when thecompound of formula (V) and the compound of formula R^(u)N⁻—S(O)₂X⁺ aremixed together, and then a suitable solvent or diluent is added. In someother embodiments, the treating of step d) I-D) occurs when the compoundof formula R^(u)N⁻—S(O)₂X⁺ is added to the compound of formula (V) in asuitable solvent or diluent. In yet some other embodiments, the treatingof step d) I-D) occurs when the compound of formula (V) is added to thecompound of formula R^(u)N⁻—S(O)₂X⁺ in a suitable solvent or diluent.

Steps d) I-D) and II-D) may be conveniently carried out in the presenceof a suitable solvent or diluent, which may be the same or different foreach of steps d) I-D), and II-D). Examples of suitable solvents are asdescribed above for steps d) I-A), II-A) and III-A). In someembodiments, steps d) I-D) and II-D) are carried out in a solventcomprising acetonitrile, N,N′-dimethylacetamide, N,N′-dimethylformamide,N-methylpyrrolidinone, dimethylsulfoxide, or mixtures thereof.

The treating of step d) I-D) is preferably performed at ambient orelevated reaction temperature. One skilled in the art will be able toselect a suitable reaction temperature and reaction time in view of thereaction conditions being used.

In some embodiments, step d) I-D) may be carried out at reactiontemperatures of at least about 0° C., 25° C. or 40° C. In someembodiments, step d) I-D) may be carried out at reaction temperatures nogreater than 55° C., 65° C. or 95° C. Any range encompassing these highand low reaction temperatures are included within the scope of theinvention. Step d) I-D) is preferably performed at reaction temperaturesin the range of about 0° C. to about 95° C., about 25° C. to about 65°C., or about 40° C. to about 55° C.

Preferably, the process for forming a compound of formula (VI) from acompound of formula (V) comprising steps d) I-D) and II-D ischaracterized by at least one of the following features:

-   -   (i) the treating of step d) I-D) is carried out in acetonitrile;        and    -   (ii) the treating of d) I-D) is performed at a reaction        temperature in the range of about 40° C. to about 55° C.

In some embodiments, the compound of formula R^(u)N⁻—S(O)₂X⁺ is formedin situ prior to the treating step d) I-C) or step d) I-D).

In some other embodiments, the compound of formula R^(u)N⁻—S(O)₂X⁺ isisolated prior to its use in step d) I-C) or step d) I-D). In some suchembodiments, formation of the compound of formula R^(u)N⁻—S(O)₂X⁺,wherein R^(u) is —C(O)OC(R^(v))₂(R^(w)), comprises the following steps:

-   -   I-E) treating (R^(w))(R^(v))₂C—OH with chlorosulfonylisocyanate;    -   II-E) treating the reaction mixture formed in step I-E) with X;        and    -   III-E) isolating the sulfamoylating reagent R^(u)NS(O)²⁻—X⁺;    -   wherein R^(v), R^(w), and X have the values and preferred values        as described above.

Steps I-E), II-E) and III-E) may be conveniently carried out in thepresence of a suitable solvent or diluent. Examples of suitable solventsare as described above for steps d) I-A), II-A) and III-A).

In some embodiments, in step I-E) the chlorosulfonylisocyanate is addedto a cooled solution of (R^(w))(R^(v))₂C—OH in a suitable solvent atsuch a rate to keep the temperature below about 10° C. In someembodiments, in step I-E), (R^(w))(R^(v))₂C—OH is added to a cooledsolution of the chlorosulfonylisocyanate in a suitable solvent at such arate to keep the temperature below about 15° C. In some embodiments, instep II-E), X is added to the reaction mixture formed in step I-E), atsuch a rate to keep the temperature below about 15° C. In someembodiments, the sulfamoylating reagent is isolated by concentrating thereaction mixture. In some other embodiments, the sulfamoylating reagentis isolated by concentrating the reaction mixture of step III-E), andthen stirring the residue in a different solvent such that a solidprecipitate is formed which can be collected by filtration and dried. Insome embodiments, the sulfamoylating reagent is directly isolated instep III-E), by filtration from the reaction mixture of step II-E).

In some embodiments, the compound of formula R^(u)N⁻—S(O)₂X⁺, isisolated as a complex further comprising the hydrochloride salt of X. Insome embodiments, the ratio of the compound of formula R^(u)N⁻—S(O)₂X⁺to the hydrochloride salt of X in the complex is less than one. In someother embodiments, the ratio of the compound of formula R^(u)N⁻—S(O)₂X⁺to the hydrochloride salt of X in the complex is about one. In someother embodiments, the ratio of the compound of formula R^(u)N⁻—S(O)₂X⁺to the hydrochloride salt of X in the complex is more than one.

In some embodiments, when R^(u) is hydrogen, the compound of formula(VI) can be directly isolated and optionally purified following step d)II-A) or step d) II-B) by methods known to one of skill in the art.

In other embodiments when R^(u) is an acid-labile protecting group, thereaction mixture is treated with an acid in step d) III-A) or step d)III-B) or step d) II-C) or step d) II-D). Mineral acids, Lewis acids,and organic acids all are suitable for use in the reaction. Examples ofmineral acids include, but are not limited to, hydrochloric acid,sulfuric acid, hydrobromic acid, nitric acid and phosphoric acid.Examples of suitable Lewis acids include, but are not limited to, SnCl₄,(CH₃)₃SiI, Mg(C₁₀₄)₂, BF₃, ZnBr₂, Sn(OTf)₂, and Ti(OiPr)₄. Examples oforganic acids include but are not limited to acetic acid, propionicacid, benzoic acid, formic acid, oxalic acid, trichloroacetic acid,trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acid andtrifluoromethanesulfonic acid.

In some other embodiments, when R^(u) is an acid-labile protectinggroup, a compound characterized by formula (VIa), wherein each ofvariables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), R^(h),R^(h′), R^(k), R^(m), R^(n), and R^(o) in formula (VIa) is as definedabove in formula (VI), can be directly isolated, and optionallypurified, following step d) II-A) or step d) II-B) or step d) I-C) orstep d) I-D), by methods known to one of skill in the art. The compoundof formula (VIa) can then be treated in a separate reaction with an acidto remove the protecting group R^(u) using the same reactions conditionsas described herein for step d) III-A) or step d) III-B) or step d)II-C) or step d) II-D), to afford the compound of formula (VI). It willbe recognized by one of skill in the art, that when R^(u) in compoundsof formula (VIa) is an acid-labile protecting group, there may bealternative deprotection conditions that will remove the R^(u) group togenerate compounds of formula (VI).

In some embodiments, wherein R^(u) is an acid labile protecting group,following removal of the acid-labile protecting group by treatment withacid, the reaction mixture is neutralized during work-up, and thecompound of formula (VI) is isolated as a free base. In suchembodiments, the compound of formula (VI) can be isolated as a solidfollowing the work-up by concentration of the solvent or diluent, andtreatment with methylene chloride, trifluorotoluene, or mixturesthereof. The resulting solid can be isolated by filtration. In someother embodiments, the compound of formula (VI) may be isolated as asalt.

In some other embodiments, when R^(u) is an amine protecting group, acompound characterized by formula (VIa) wherein each of variables R^(a),R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), R^(h), R^(h′), R^(k), R^(m),R^(n), and R^(o) in formula (VIa) is as defined above in formula (VI),can be directly isolated, and optionally purified, following step d)II-A) or step d) II-B) or step d) I-C) or step d) I-D), by methods knownto one of skill in the art. The compound of formula (VIa) can then beconverted to the compound of formula (VI) by removal of the amineprotecting group R^(u), by methods known to one of the skill in the art.

With respect to the compounds and the processes described herein, thefollowing preferred values are applicable.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI), each of R^(b),R^(h) and R^(h′) is independently hydrogen, fluoro, C₁₋₄ aliphatic orC₁₋₄ fluoroaliphatic. In some embodiments, each of R^(b), R^(h) andR^(h′) is independently hydrogen, fluoro, methyl, ethyl ortrifluoromethyl. In preferred embodiments, each of R^(b), R^(h) andR^(h′) is hydrogen.

In formulas (I), (Ia), (II), (IV), (V) and (VI), R^(d) is hydrogen,fluoro, C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic. In some embodiments,R^(d) is hydrogen, fluoro, methyl, ethyl or trifluoromethyl. Inpreferred embodiments, R^(d) is hydrogen.

In formula (IIa), R^(d′) is hydrogen, fluoro, bromo, C₁₋₄ aliphatic orC₁₋₄ fluoroaliphatic. In some embodiments, R^(d′) is hydrogen, fluoro,methyl, ethyl or trifluoromethyl. In other embodiments, R^(d′) ishydrogen or bromo. In some preferred embodiments, R^(d′) is hydrogen. Insome other preferred embodiments, R^(d′) is bromo.

In formulas (I), (Ia), (II), (IV), (V) and (VI), each R^(f)independently is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic. In some embodiments, each R^(f) is independentlyhydrogen, fluoro, methyl, ethyl or trifluoromethyl. In preferredembodiments, each R^(f) is hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V), (VI), each of R^(e) andR^(e′) is independently hydrogen or C₁₋₄ aliphatic. In some embodiments,each of R^(e) and R^(e′) is independently hydrogen, methyl or ethyl. Inpreferred embodiments, each of R^(e) and R^(e′) is hydrogen.

In formulas (I), (Ia), (III), (IV), (V) and (VI), R^(k) is hydrogen orC₁₋₄ aliphatic. In some embodiments, R^(k) is hydrogen, methyl or ethyl.In preferred embodiments, R^(k) is hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI), R^(c) ishydrogen, fluoro, chloro, —OH, —O—R^(m) or optionally substituted C₁₋₄aliphatic. In some embodiments, R^(c) is hydrogen, —OH, fluoro ormethyl. In preferred embodiments, R^(c) is hydrogen, —OH or —O—R^(m). Inmore preferred embodiments, R^(c) is hydrogen or —OH. In other morepreferred embodiments, R^(c) is hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI), R^(a) and R^(j)are each independently hydrogen or a hydroxyl protecting group, andR^(m) is a hydroxyl protecting group. R^(a) may be taken together withR^(j) and the intervening atoms to form a cyclic diol protecting group,or R^(a) may be taken together with R^(m) and the intervening atoms toform a cyclic diol protecting group, or R^(j) may be taken together withR^(m) to form a cyclic diol protecting group. Preferred values forhydroxyl protecting groups and cyclic diol protecting groups are givenbelow.

In some embodiments, R^(a) is hydrogen. In some embodiments R^(j) ishydrogen. In certain particular embodiments both R^(a) and R^(j) arehydrogen.

In some embodiments, the hydroxyl protecting group is selected from thegroup consisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa), where R^(aa) is optionallysubstituted C₁₋₄ aliphatic or optionally substituted aryl.

In some embodiments, the silyl protecting group is selected fromtrimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Insome embodiments, the optionally substituted C₁₋₄ aliphatic protectinggroup is selected from methoxymethyl, benzyl (Bn), p-methoxybenzyl(PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and thelike. In some embodiments, the —C(O)—R^(aa) protecting group is selectedfrom acetyl, formyl, pivaloyl, benzoyl and the like. In someembodiments, the —C(O)—O—R^(aa) protecting group is selected frombenzyloxycarbonyl (Cbz), methoxycarbonyl, tert-butoxycarbonyl (t-Boc),fluorenylmethoxycarbonyl (Fmoc) and the like.

In some embodiments, the cyclic diol protecting group is a 1,2-cyclicdiol protecting group. In some embodiments, the cyclic diol protectinggroup is a 1,3-cyclic diol protecting group. In some other embodiments,the cyclic diol protecting group is —C(R^(aa))(R^(bb))—, where R^(aa) isoptionally substituted C₁₋₄ aliphatic or optionally substituted aryl,and R^(bb) is hydrogen or optionally substituted C₁₋₄ aliphatic. In somepreferred embodiments, R^(aa) is hydrogen or methyl. In some preferredembodiments, R^(bb) is methyl, phenyl or 4-methoxyphenyl.

In formulas (I), (II) and (IV), R^(g) is chloro, fluoro, iodo or bromo.In some preferred embodiments, R^(g) is chloro or fluoro. In certainpreferred embodiments, R^(g) is chloro.

In formula (Ia), R^(g′) is halogen, —O—R^(s), —S—R^(t), —S(O)R^(t) or—S(O)₂R^(t); wherein R^(s) is C₁₋₄ aliphatic, alkylsulphonyl,fluoroalkylsulphonyl, optionally substituted aryl or optionallysubstituted arylsulphonyl, and R^(t) is optionally substituted C₁₋₄aliphatic or optionally substituted aryl. In some embodiments, R^(g′) ischloro, fluoro, iodo, methoxy, ethoxy, substituted or unsubstitutedphenoxy, mesylate (—OSO₂CH₃), tosylate (—OSO₂C₆H₄CH₃), triflate(—OSO₂CF₃), methylsulfonyl and benzylsulfonyl. In preferred embodiments,R^(g′) is chloro, fluoro, bromo, mesylate, tosylate or triflate.

In formulas (II) and (IV), R^(l) is —CH₂—CHO or —CH₂CH(OR^(l′))₂,wherein each R^(l′) is independently C₁₋₆ aliphatic, or two R^(l′) aretaken together with the intervening oxygen and carbon atoms to form anoptionally substituted 5- or 6-membered cyclic acetal moiety. In someembodiments, two R^(l′) are taken together with the intervening oxygenand carbon atoms to form an optionally substituted 5- or 6-memberedcyclic acetal moiety. In some such embodiments, two R^(l′), takentogether with the intervening oxygen and carbon atoms, form anoptionally substituted 1,3-dioxane or 1,3-dioxolane moiety. In someother embodiments each R^(l′) independently is C₁₋₃ aliphatic. Incertain particular embodiments each R^(l′) is methyl or ethyl.

In amines of formula HNR^(n)R^(o) and in compounds of formulas (V) and(VI), R^(n) is hydrogen or C₁₋₄ aliphatic. In some embodiments, R^(n) ishydrogen, methyl or ethyl. In preferred embodiments, R^(n) is hydrogen.

In amines of formula HNR^(n)R^(o), and in formulas (V) and (VI), R^(o)is optionally substituted C₁₋₁₀ aliphatic, aryl, heteroaryl orheterocyclic. In some embodiments, R^(o) is optionally substituted C₁₋₁₀aliphatic. In some embodiments, R^(o) is an optionally substitutedcycloaliphatic or heterocyclic ring. In other embodiments, R^(o) is anaryl or heteroaryl ring. In certain embodiments, R^(o) is a mono-, bi-or tricyclic ring system. In some other certain embodiments, R^(o) is amono- or bicyclic ring system.

In some such embodiments, the ring represented by R^(o) is selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl,indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,bicycloheptenyl and bicyclooctanyl. In certain embodiments, the ringrepresented by R^(o) is an optionally substituted indanyl,tetrahydronaphthyl, or chromanyl.

In such embodiments, the ring or ring system represented by R^(o) may beoptionally substituted on either or both of its component rings and thesubstitutents may be the same or different. In particular, eachsubstitutable unsaturated ring carbon is unsubstituted or substitutedwith 0-2 R^(p) and each substitutable saturated ring carbon isunsubstituted or substituted with 0-2 R^(q). The variables R^(p) andR^(q) have the values described below.

Each R^(p) independently is selected from the group consisting offluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)).

Each R^(q) independently is selected from the group consisting offluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), provided that when two R^(q) are attached to thesame carbon atom, one must be selected from the group consisting offluoro, —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)), and C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or two R^(q)on the same carbon atom together form ═O or ═C(R^(5x))₂.

R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ar(C₁₋₄)alkyl, the aryl portion of which may be optionally substituted,and R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀ar(C₁₋₄)alkyl, the aryl portion of which may be optionally substituted,or an optionally substituted 5- or 6-membered aryl, heteroaryl, orheterocyclyl ring; or R^(4x) and R^(4y), taken together with thenitrogen atom to which they are attached, form an optionally substituted4- to 8-membered heterocyclyl ring having, in addition to the nitrogenatom, 0-2 ring heteroatoms independently selected from N, O, and S. EachR^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or anoptionally substituted C₆₋₁₀ aryl or C₆₋₁₀ ar(C₁₋₄)alkyl.

In some embodiments, in amines of formula HNR^(n)R^(o), and in formulas(V), (VI), (VIa) and (VIb) the ring or ring system represented by R^(o)is represented by formula (VII):

wherein, the variables R^(p) and R^(q) have the values described above.

In some other embodiments, in amines of formula HNR^(n)R^(o) and informulas (V), (Va), (VI), (VIa), (VIb), (VIc) and (VId), the ring orring system represented by R^(o) is selected from the group consistingof:

In certain particular embodiments, in amines of formula HNR^(n)R^(o) andin formulas (V), (Va), (VI), (VIa), (VIb), (VIc) and (VId), the ring orring system represented by R^(o) is selected from the group consistingof:

In a particular embodiment, the invention relates to a process for theformation of a subgenus of the compounds of formula (VI), characterizedby formula (VIb):

or a pharmaceutically acceptable salt thereof; wherein:

stereochemical configurations depicted at asterisk positions indicaterelative stereochemistry;

the variables R^(a), R^(b), R^(c), R^(d), R^(n), and R^(o) have thevalues and preferred values described above for formulas (I)-(VI); and

the process comprises steps (a)-(d) as described above for the formationof compounds of formula (VI). Preferred conditions for each of steps(a)-(d) are as described above for the formation of compounds offormulas (I)-(VI).

In another particular embodiment, the invention relates to a process forthe formation of a subgenus of the compounds of formula (VI),characterized by formula (VIc):

or a pharmaceutically acceptable salt thereof; wherein:

stereochemical configurations depicted at asterisk positions indicaterelative stereochemistry;

the variables R^(a), R^(b), R^(c), R^(d), R^(p), and R^(q) have thevalues and preferred values described above for formulas (I)-(VI); and

the process comprises steps a)-d) as described above for the formationof compounds of formula (VI). Preferred conditions for each of stepsa)-d) are as described above for the formation of compounds of formulas(I)-(VI).

In another particular embodiment, the invention relates to a process forthe formation of a subgenus of the compounds of formula (VI),characterized by formula (VId):

or a pharmaceutically acceptable salt thereof; wherein:

stereochemical configurations depicted at asterisk positions indicaterelative stereochemistry;

the variables R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), R^(h),R^(h′), R^(k), R^(p), and R^(q) have the values and preferred valuesdescribed above for formulas (I)-(VII); and

the process comprises steps a)-d) as described above for the formationof compounds of formula (VI). Preferred conditions for each of stepsa)-d) are as described above for the formation of compounds of formulas(I)-(VI).

Another aspect of the invention relates to compounds which are usefulintermediates in the processes described above, such as compounds offormula (Ia) and formula (IIa).

One embodiment relates to compounds of formula (Ia):

or a salt thereof;

wherein stereochemical configurations depicted at asterisk positionsindicate absolute stereochemistry;

R^(a) is hydrogen or a protecting group; or R^(a) taken together withR^(j) and the intervening atoms forms a cyclic diol protecting group; orR^(a) taken together with R^(m) and the intervening atoms forms a cyclicdiol protecting group;

R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic;

R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionallysubstituted C₁₋₄ aliphatic;

R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic;

R^(e) is hydrogen or C₁₋₄ aliphatic;

R^(e′) is hydrogen or C₁₋₄ aliphatic;

each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic;

R^(g′) is a leaving group;

R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) takentogether with R^(a) and the intervening atoms forms a cyclic diolprotecting group;

R^(k) is hydrogen or C₁₋₄ aliphatic; and

R^(m) is a hydroxyl protecting group; or R^(m) taken together with R^(a)and the intervening atoms forms a cyclic diol protecting group.

In some embodiments, the compound of formula (Ia) is characterized byformula (Iaa):

wherein stereochemical configurations depicted at asterisk positionsindicate absolute stereochemistry;

R^(g′) is chloro, bromo, fluoro, iodo, —O—R^(s), —S—R^(t), —S(O)R^(t) or—S(O)₂R^(t);

wherein R^(s) is C₁₋₄ aliphatic, alkylsulphonyl, fluoroalkylsulphonyl,optionally substituted aryl or optionally substituted arylsulphonyl; and

R^(t) is optionally substituted C₁₋₄ aliphatic or optionally substitutedaryl.

In certain embodiments, the compound of formula (Ia) is characterized byformula (Iaa) wherein R^(c) is hydrogen, —OH or —O—R^(m);

R^(a) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa), or R^(a) taken together withR^(j) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—; or R^(a) taken together with R^(m) and theintervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(j) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(j) taken together withR^(a) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(m) is a hydroxyl protecting group selected from the group consistingof a silyl protecting group, optionally substituted aliphatic,—C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(m) taken together with R^(a) andthe intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(aa) is optionally substituted C₁₋₄ aliphatic or optionallysubstituted aryl; and

R^(bb) is hydrogen or optionally substituted C₁₋₄ aliphatic.

In certain other preferred embodiments, the compound of formula (Ia) ischaracterized by formula (Iaa) and values and preferred values forR^(a), R^(j), R^(m), R^(c), and R^(g′) are as described above.

Another aspect of this invention relates to compounds of formula (IIa):

or a salt thereof; wherein:

stereochemical configurations depicted at asterisk positions indicatesabsolute stereochemistry;

R^(a) is hydrogen or a protecting group; or R^(a) taken together withR^(j) and the intervening atoms forms a cyclic diol protecting group; orR^(a) taken together with R^(m) and the intervening atoms forms a cyclicdiol protecting group;

R^(b) is hydrogen, fluoro, C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic;

R^(c) is hydrogen, fluoro, chloro, —OH, —O—R^(m) or optionallysubstituted C₁₋₄ aliphatic;

R^(d′) is hydrogen, fluoro, bromo, C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic;

R^(e) is hydrogen or C₁₋₄ aliphatic;

R^(e′) is hydrogen or C₁₋₄ aliphatic;

R^(h) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

R^(h′) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

R^(j) is hydrogen or a hydroxyl protecting group; or R^(j) takentogether with R^(a) and the intervening atoms forms a cyclic diolprotecting group;

R^(m) is a hydroxyl protecting group; or R^(m) taken together with R^(a)and the intervening carbon atoms forms a cyclic diol protecting group;and

R^(r) is hydrogen or an amine protecting group.

In some embodiments, the compound of formula (IIa) is characterized byformula (IIaa):

wherein, stereochemical configurations depicted at asterisk positionsindicate absolute stereochemistry; and

R^(c) is hydrogen, —OH or —O—R^(m);

R^(a) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa), or R^(a) taken together withR^(j) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—; or R^(a) taken together with R^(m) and theintervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(j) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(j) taken together withR^(a) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(m) is a hydroxyl protecting group selected from the group consistingof a silyl protecting group, optionally substituted aliphatic,—C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(m) taken together with R^(a) andthe intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(aa) is optionally substituted C₁₋₄ aliphatic or optionallysubstituted aryl;

R^(bb) is hydrogen or optionally substituted C₁₋₄ aliphatic; and

R^(r) is hydrogen or an amine protecting group.

In some other embodiments, the compound of formula (IIa) ischaracterized by formula (IIbb):

wherein stereochemical configurations depicted at asterisk positionsindicate absolute stereochemistry; and

R^(d′) is bromo;

R^(a) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa), or R^(a) taken together withR^(j) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—; or R^(a) taken together with R^(m) and theintervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(j) is hydrogen or a hydroxyl protecting group selected from the groupconsisting of a silyl protecting group, optionally substitutedaliphatic, —C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(j) taken together withR^(a) and the intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(m) is a hydroxyl protecting group selected from the group consistingof a silyl protecting group, optionally substituted aliphatic,—C(O)—R^(aa) and —C(O)—O—R^(aa); or R^(m) taken together with R^(a) andthe intervening atoms forms a cyclic diol protecting group—C(R^(aa))(R^(bb))—;

R^(aa) is optionally substituted C₁₋₄ aliphatic or optionallysubstituted aryl;

R^(bb) is hydrogen or optionally substituted C₁₋₄ aliphatic; and

R^(r) is hydrogen or an amine protecting group.

In certain preferred embodiments, the compound of formula (Ia) ischaracterized by formulas (IIaa) and (IIbb) and values and preferredvalues for R^(a), R^(j), R^(m), R^(c), and R^(d′) are as describedabove.

In formulas (IIa), (IIIaa), and (IIbb), R^(r) is hydrogen or an amineprotecting group. In some embodiments, R^(r) is hydrogen. In otherembodiments, R^(r) is an amine protecting group selected from—C(O)R^(cc), —C(O)—OR^(cc), —CH₂R^(cc) and —C(R^(cc))₃, wherein R^(cc)is optionally substituted C₁₋₄ aliphatic or optionally substituted aryl.In preferred embodiments R^(r) is hydrogen, benzyl, 4-methoxybenzyl,tert-butoxycarbonyl, triphenylmethyl or (4-methoxyphenyl)diphenylmethyl.In certain preferred embodiments, R^(r) is tert-butoxycarbonyl ortriphenylmethyl.

In particular embodiments, the invention relates to a compound selectedfrom the group consisting of:

wherein stereochemical configurations depicted at asterisk positionsindicate absolute stereochemistry; and

R^(r) is —C(O)R^(cc), —C(O)—OR^(cc), —CH₂R^(cc) or —C(R^(cc))₃, whereinR^(cc) is optionally substituted C₁₋₄ aliphatic or optionallysubstituted aryl.

In some embodiments the compound of formula (IIa) has adiastereoisomeric purity of at least 80%, 90%, 95% or 99%. In some otherembodiments the compound of formula (IIa) has an enantiomeric purity ofat least 80%, 90%, 95% or 99%.

In some embodiments, the stereochemical configurations depicted atasterisked positions in any preceding formula indicate relativestereochemistry. In other embodiments, stereochemical configurationsdepicted at asterisked positions indicate absolute stereochemistry. Incertain particular embodiments, the invention relates to compounds offormula wherein the stereochemical configurations depicted at asteriskedpositions indicate absolute stereochemistry.

General Synthetic Methodology

Compounds of formula (II), (IIa), (III) and R^(u)NHS(O)₂Cl can beprepared by methods known to one of ordinary skill in the art and/or byreference to the schemes shown below and the synthetic examples thatfollow. Exemplary synthetic routes are set forth in Schemes 1, 2 and 3below, and in the Examples.

Scheme 1 and 2 show general routes for preparing compounds of formula(IIa), wherein each of R^(b), R^(d), R^(e), R^(e′), R^(h), and R^(h′) ishydrogen. Those of ordinary skill in the art will recognize thatcompounds of formula (IIa) wherein one or more of R^(b), R^(d), R^(e),R^(e′), R^(h), and R^(h′) is other than hydrogen can also be prepared bythe same general route beginning with appropriate starting materialsanalogous to i.

Lactams such as (−)-i are commercially available, and conversion ofcompounds of formula i to those of formula iii is accomplished bymethods such as those detailed in Scheme 1 (see Smith et al.Tetrahedron. Lett., 2001, 42, 1347). Treatment of lactam i with thionylchloride in methanol affords ii which is then protected with a suitableamino protecting group R^(r) to give compounds of formula iii (MethodA). Alternatively, protection of the amino group can occur first,followed by acid catalyzed ring-opening with a suitable acid such ashydrochloric acid in methanol to give compounds of formula iii (MethodB; see Bray et al. Tetrahedron Lett., 1995, 36, 4483). Compounds offormula iii also serve as the starting material in the alternate generalsynthesis of compounds of formula (IIa) detailed below in Scheme 2.

Base mediated hydrolysis of the ester in compounds of formula iii formscompounds of formula iv with epimerization. This transformation may beconducted using an appropriate base such as sodium hydroxide inappropriate solvents such as tetrahydrofuran and methanol (Method C).Bromination and lactonization to generate compounds of formula v (MethodD) may be effected by treatment of compounds of formula iv withtetrabutylammonium hydroxide, followed by treatment with bromine in anappropriate solvent such as methylene chloride or tetrahydrofuran. Priorto the treatment with bromine the reaction mixture is cooled to anappropriate temperature in the range of about 0° C. to −70° C. Thereaction mixture is kept below about 20° C. during the course of thereaction. Other reagents that can be used instead of tetrabutylammoniumhydroxide, prior to the addition of bromine, include, but are notlimited to, sodium hydrogen carbonate, potassium phosphate, pyridine, ormixtures thereof. Other suitable solvents for this transformationinclude, but are not limited to, ethyl acetate, methanol, water,dimethoxyethane, or mixtures thereof.

Reduction of the lactone in compounds of formula v with a reducing agentyields compounds of formula vi (Method E). Suitable reducing agents forthis transformation include lithium tetrahydroborate. Appropriatesolvents for this transformation include tetrahydrofuran, diethyl etherand the like. The solution of compounds of formula v is generallycooled, preferably in the range of about −20° C. to 0° C. prior to theaddition of the reducing agent. A second reagent, such as, but notlimited to, copper chloride, or palladium chloride may also be employedin addition to the lithium tetrahydroborate. Other suitable reagents forthe transformation of compounds of formula v to those of formula viinclude lithium aluminium hydride, diisobutylaluminium hydride, andsodium borohydride. Other suitable solvents for this transformationinclude isopropanol, methanol, and dimethylsulfoxide which may containup to about 10% water. Other suitable temperatures ranges for thistransformation are in the range of about 0° C. to about 40° C.

Removal of the protecting group R^(r) and de-bromination in compounds offormula vi (Method F) then affords compound vii. These transformationscan be accomplished in a number of ways known to one of ordinary skillin the art, depending on the protecting group R^(r) that is used. Insome embodiments, R^(r) is a hydrogen-labile protecting group. In suchembodiments deprotection and de-bromination are accomplished in a singlestep. This may include treatment with hydrogen gas in the presence of apalladium catalyst in an appropriate solvent such as methanol. Thistransformation yields compounds of formula vii as their hydrobromidesalts. In other embodiments, removal of the protecting group R^(r) andde-bromination may be accomplished in separate steps. In someembodiments the hydrochloride salts of compounds of formula vii can begenerated.

When the protecting group R^(r) is acid-labile, following its removalwith HBr or HCl, the hydrobromide or hydrochloride salt of the compoundof formula vi, where R^(r) is H, is generated. This compound is thentreated with hydrogen to accomplish de-bromination and yield thecompound of formula vii. The debromination can be accomplished using asuitable palladium catalyst, a suitable base and a suitable solvent.Suitable catalysts include Pd/C. Suitable bases include, but are notlimited to, triethylamine, N,N′-diisopropylethylamine, pyridine,tetrabutylammonium hydroxide and sodium hydrogen carbonate. Suitablesolvents include, but are not limited to, isopropyl alcohol andmethanol.

Scheme 2 details an alternate general route for the synthesis ofcompounds of general formula (IIa) wherein each of R^(b), R^(d), R^(e),R^(e′), R^(h), and R^(h′) is hydrogen. The starting material iii can beprepared as detailed in Scheme 1 above. Conversion of compounds offormula iii to compounds of formula viii can be accomplished bytreatment with diazabicyclo[5.4.0]undec-7-ene (Method G) in anappropriate solvent such as methylene chloride (see Bray et al.Tetrahedron Lett., 1995, 36, 4483).

Reduction of the ester group in compounds of formula viii to givecompounds of formula ix is accomplished by treatment with a suitablereducing agent such as diisobutylaluminium hydride or the like in anappropriate solvent such as toluene or tetrahydrofuran (Method H). Thesolution of compounds of formula viii is generally cooled, preferably inthe range of about −20° C. to about 0° C. prior to the addition of thereducing agent.

Epoxidation of the double bond in compounds of formula ix to generatecompound of formula x is achieved by known methods (Method J) (see Gaoet al. J. Am. Chem. Soc., 1987, 5765). A solution of the compound offormula ix is added slowly to a cooled mixture of (+)-diethyl-L-tartrateand titanium (IV) isopropoxide in methylene chloride. The rate ofaddition of compounds of formula ix is such that the reactiontemperature is maintained in range of about −25° C. to about −45° C. Tothis, tert-butyl hydroperoxide is added slowly such that the reactiontemperature is maintained in range of about −25° C. to about −45° C.

Regiospecific ring opening of the epoxide in compounds of formula x toafford compounds of formula xi can be accomplished by treatment of asolution of the compound of formula x with sodium borohydride andborane-THF complex (see Brown and Yoon J. Am. Chem. Soc., 1968, 90,2686) in an appropriate solvent such as methylene chloride (Method K).

The reaction to generate compounds of formula xi may also generateamounts of compounds of formula xii as a minor product. The primaryalcohol in compounds of formula xi may be selectively protected with abulky protecting group (R^(j)) such as triisopropylsilyl ortert-butyldiphenylsilyl to afford compounds of formula xiii which can beseparated from compounds of formula xii by purification methods known toone of ordinary skill in the art, such as column chromatography. Theintroduction of the silyl protecting group may be effected by knownmethods such as treatment with the appropriate silyl chloride in thepresence of a base such as triethylamine or N,N′-diisopropylethylaminein a solvent such as methylene chloride (Method L).

Following purification, the silyl protecting group may be selectivelyremoved from compounds of formula xiii to give compounds of formula xiv.This transformation may be accomplished by treatment of a cooledsolution of a compound of formula xiii with a solution oftetrabutylammonium fluoride (TBAF) in an appropriate solvent such astetrahydrofuran (Method M).

Removal of the protecting group R^(r) affords compounds of formula vii(Method F). This transformation can be accomplished in a number of waysknown to one of ordinary skill in the art depending on the protectinggroup R^(r) that is used. For example, in some embodiments, theprotecting group R^(r) is subject to hydrogenolysis, and deprotectioncan be effected by treatment with hydrogen gas in the presence of apalladium catalyst (Method F) in an appropriate solvent such asmethanol. In some other embodiments, the protecting group R^(r) isacid-labile and deprotection can be effected by an acid.

Either or both of the hydroxyl groups in compounds of formula vi, vii orxiv in Schemes 1 or 2 may be protected with a hydroxyl protecting groupor a cyclic diol protecting group using methods known to one of ordinaryskill in the art.

Compounds of formula (III) may be prepared according to methods such asthat described by J. A. Montgomery and K. Hewson, J. Med. Chem., 1967,10, 665.

Scheme 3 shows a general routes for preparing compounds of formulaR^(u)NHS(O)₂Cl wherein R^(u) is —C(O)OC(R^(v))₂(R^(w)) and R^(w) isphenyl. Those of ordinary skill in the art will recognize that compoundsof formula R^(u)NHS(O)₂Cl wherein R^(w) is other than phenyl can also beprepared by the same general route beginning with appropriate startingmaterials analogous to xv.

Starting from a commercially available methylbenzoate xv, treatment witha Grignard reagent R^(v)MgCl in an appropriate solvent such astetrahydrofuran affords compounds of formula xvi (Method N). Thesolution of the compounds of formula xv is cooled to about 0° C. priorto the addition of the Grignard reagent which is added at a ratesufficient to keep the temperature of the reaction mixture below about10° C. A solution of xvi is then added to a cooled solution ofchlorosulfonyl isocyanate in an appropriate solvent such astetrahydrofuran to afford compounds of formula xvii. The addition of thesolution of compounds of formula xvi is at a rate sufficient to keep thetemperature of the reaction mixture below about 10° C. (Method O). Theresulting substituted-(chlorosulfonyl)carbamate reagent xvii is thenstored with as a solution in an appropriate solvent such astetrahydrofuran until use.

The compound of formula R^(u)NHS(O)₂Cl wherein R^(u) is —C(O)OC(CH₃)₃,may be prepared according to methods such as that described in Hirayamaet al. Bioorg. Med. Chem., 2002, 10, 1509-1523. The compound of formulaR^(u)NHS(O)₂Cl wherein R^(u) is —C(O)N(Ph)₂ may be prepared in a mannersimilar to that described in U.S. Pat. Appl. Publ. (2005), US 2005282797A1.

The amines used in Example 18 can be made by methods disclosed inLangston S. et al. U.S. patent application Ser. No. 11/700,614, which ishereby incorporated by reference in its entirety.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examplesillustrate how to make or test specific compounds, and are not to beconstrued as limiting the scope of the invention in any way.

EXAMPLES ABBREVIATIONS

AcOH acetic acid

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Boc tert-butoxycarbonyl

DCM methylene chloride

DI deionized

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMF-DMA dimethylformamide dimethylacetal

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH ethanol

iPrOAc isopropyl acetate

MCPBA meta-chloroperbenzoic acid

MeOH methanol

MTBE methyl tert-butyl ether

THF tetrahydrofuran

h hours

HRMS high resolution mass spectrum

min minutes

m/z mass to charge

MS mass spectrum

RP LC-MS reverse phase liquid chromatography-mass spectrometry

TLC thin-layer chromatography

Proton nuclear magnetic resonance spectra were obtained on a VarianMercury 300 spectrometer at 300 MHz, on a Bruker AVANCE 300 spectrometerat 300 MHz, or on a Bruker AVANCE 500 spectrometer at 500 MHz.

LCMS conditions: spectra were run on a Phenomenex Luna 5μ C18(2) 150×4.6mm column on an Agilent 1100 series instrument at 1 ml/min for a 20minute run using the following gradients:

Method Formic Acid (FA): Mobile phase A consisting of 99% v/v water, 1%v/v acetonitrile, 0.1% v/v formic acid. Mobile phase B consisting of 95%v/v acetonitrile, 5% v/v water, 0.1% v/v formic acid. Method follows agradient of 5% B to 100% B over 12 minutes, maintaining at 100% B for 3minutes and returning to 5% B over 1 minute and maintaining until end ofmethod.

Method Ammonium Acetate (AA): Mobile phase A consisting of 100% water(with 10 mM ammonium acetate, pH=4.5). Mobile phase B consisting of 95%v/v acetonitrile, 5% v/v water (with 10 mM ammonium acetate, pH=4.5).Method follows a gradient of 5% B to 100% B over 12 minutes, maintainingat 100% B for 3 minutes and returning to 5% B over 1 minute andmaintaining 5% B until end of run.

Thin-layer chromatography (TLC) was performed using EMD silica-gel 60plates and visualized by ultraviolet (UV) light.

HPLC analyses were run on a Phenomenex Luna 5μ C18(2) 150×4.6 mm columnon an Agilent 1100 series instrument at 1.0 ml/min for a 30 minute runusing the following gradients:

Method Ammonium Acetate (AA2): Mobile phase A consisting of 100% water(with 10 mM ammonium acetate, pH=4.5). Mobile phase B consisting of 95%v/v acetonitrile, 5% v/v water (with 10 mM ammonium acetate, pH=4.5).Method follows a gradient of 30% B to 70% B over 12 minutes, form 70% Bto 100% B over 5 minutes maintaining at 100% B for 3 minutes andreturning to 30% B over 5 minutes and maintaining 30% B until end ofrun.

Example 1: Methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylateHydrochloride

(−)-2-Azabicyclo[2,2,1]hept-5-en-3-one (20.00 g, 0.1833 mmol) wasdissolved in MeOH (140 mL) and this mixture was cooled to 0° C. Thionylchloride (29.4 mL, 0.403 mol) was then added dropwise, keeping thetemperature less than 15° C. Upon completion of addition, the mixturewas left to stir at 5° C. for 2 hours. The solvent was removed underreduced pressure to yield an oil, which was dried further under highvacuum overnight at 35° C. to afford the title compound as a white solid(33 g) which was used without further purification. ¹H NMR (300 MHz,DMSO, δ): 8.45 (s, 3H), 6.03 (m, 1H), 5.87 (m, 1H), 4.13 (m, 1H), 3.60(m, 4H), 2.53 (m, 1H) and 1.89 (m, 1H).

Example 2: Methyl (1S,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylate

Methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (5.50g) was suspended in methylene chloride (60 mL), to which triphenylmethylchloride (9.06 g, 0.0325 mol) was added. The mixture was then cooled to0° C. Triethylamine (10.8 mL, 0.0774 mol) was then added dropwisekeeping the temperature less than 10° C. Upon completion of addition,the mixture was allowed to warm to 20-25° C. The mixture was left tostir at 20-25° C. for 17 hours. The mixture was then washed with water(3×50 mL). The aqueous washes were combined and extracted with DCM (50mL). The organics were combined and washed with brine (20 mL) and thesolvent was removed under reduced pressure to afford the title compoundas a brown oil (12.5 g) which was used without further purification. ¹HNMR (300 MHz, CDCl₃, δ): 7.58 (m, 6H), 7.27 (m, 6H), 7.18 (m, 3H), 5.57(m, 1H), 4.93 (m, 1H), 3.76 (m, 1H), 3.65 (s, 3H), 3.18 (m, 1H), 2.11(m, 1H), 1.90 (m, 1H) and 1.53 (m, 1H).

Example 3: (1R,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylic Acid

Methyl (1S,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylate (11.00 g,0.02868 mol) was dissolved in tetrahydrofuran (50 mL) and methanol (50mL). Sodium hydroxide (2.06 g, 0.0516 mol) in water (60 mL) was addedand the mixture stirred at ambient temperature for 18 hours. TLC (20%EtOAc/Hexane) showed no starting material. 20% w/v citric acid in waterwas added dropwise at ambient temperature until the mixture was pH 6.The mixture was then extracted with methylene chloride (3×100 mL). Theorganic layers were combined and dried over Na₂SO₄, filtered andconcentrated to give a white foam (10 g). TLC (50% EtOAc/Hexane) shows 2diastereomers. The mixture was purified using column chromatography,eluting with 50% EtOAc/Hexane to afford the title compound (1.3 g) as awhite solid. ¹H NMR (300 MHz, DMSO, δ): 7.47 (m, 6H), 7.30 (m, 6H), 7.17(m, 3H), 5.49 (m, 1H), 4.88 (m, 1H), 3.70 (m, 1H), 3.35 (m, 1H), 1.84(m, 1H) and 1.43 (m, 1H). LCMS: R_(f)=12.95 mins, ES⁺=370 (AA).

Example 4:(1R,3R,4R,5R)-4-bromo-3-(tritylamino)-6-oxabicyclo[3.2.0]heptan-7-one

To (1R,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylic acid (0.9 g,0.0024360 mol) dissolved in methylene chloride (20 mL), was added 31%tetrabutylammonium hydroxide in MeOH (2.579 mL), and the mixture wasstirred for 30 minutes at ambient temperature. The mixture wasconcentrated under reduced pressure. The resultant residue was thendissolved in methylene chloride (20 mL, 0.3 mol) and cooled to −70° C.under a blanket of N₂. Bromine (251 uL, 0.00487 mol) in 5 ml ofmethylene chloride was then added dropwise and the mixture was stirredat −70° C. for 1 hour, then warmed to 0° C. Upon reaching 0° C., 20 mLof 5% w/v Na₂SO₃ in water was added dropwise and mixture was allowed towarm to ambient temperature. The reaction mixture was extracted withmethylene chloride (3×10 mL), organic layers were combined and driedover Na₂SO₄, filtered and concentrated to give a red residue. Theresidue was filtered through a silica gel plug, eluting with 0 to 30%EtOAc/Hexane to remove inorganics and impurities to afford the titlecompound (0.73 g) as a white solid. ¹H NMR (300 MHz, DMSO, δ): 7.49 (m,6H), 7.24 (m, 9H), 4.95 (d, 1H), 3.91 (m, 1H), 3.65 (m, 1H), 2.97 (m,1H), 2.66 (m, 1H), 1.62 (m, 1H) and 1.20 (m, 1H). LCMS: R_(f)=14.40mins, ES⁺Na=470 (AA).

Example 5:(1R,2R,3R,5S)-2-bromo-5-(hydroxymethyl)-3-(tritylamino)cyclopentanol

(1R,3R,4R,5R)-4-bromo-3-(tritylamino)-6-oxabicyclo[3.2.0]heptan-7-one(0.6 g, 0.0013382 mol) was dissolved in diethyl ether (20 mL) and themixture was cooled to 0° C. Lithium tetrahydroborate (0.087 g, 0.004015mol) was added in one portion and the mixture was stirred at 0° C. for 1hour, then allowed to warm to ambient temperature and stirred for afurther 1 hour. TLC (20% EtOAc/Hexane) showed no starting material. Thereaction mixture was cooled to 0° C. at which point saturated NH₄Cl aq(20 mL) was added dropwise maintaining a temperature less than 5° C. Themixture was allowed to warm to ambient temperature and extracted withmethylene chloride (3×20 mL). The organics were combined and dried overNa₂SO₄, filtered and concentrated to afford the title compound (0.61 g)as a white solid which was used without further purification. ¹H NMR(300 MHz, CD₃OD, δ): 7.56 (m, 6H), 7.25 (m, 9H), 4.15 (m, 1H), 3.55 (m,1H), 3.40 (m, 2H), 2.90 (m, 1H), 2.53 (m, 1H) and 1.63 (m, 2H). LCMS:R_(f)=13.30 mins, ES⁺Na=474 (AA).

Example 6: (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol.HBr

(1R,2R,3R,5S)-2-bromo-5-(hydroxymethyl)-3-(tritylamino)cyclopentanol(0.4 g, 0.0008842 mol) was dissolved in MeOH (10.0 mL). To this mixturewas added 5% palladium on charcoal, (0.28 g). The resulting mixture wasstirred under a balloon of hydrogen (1000 mL, 0.04 mol) for 18 hours at40° C. An aliquot was syringe filtered and concentrated. ¹H NMRindicated that the reaction had gone to completion so the entirereaction mixture was filtered through a pad of celite and the filtrateconcentrated. This sticky solid was triturated with 5 mL of THF,filtered and the bed washed with tert-butylmethyl ether. The resultingsolid was dried under vacuum at ambient temp to afford the titlecompound (0.125 g) as a white solid which was used without furtherpurification. ¹H NMR (300 MHz, CD₃OD, δ): 4.38 (t, J=4.08 Hz, 1H), 3.82(m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 2.31 (m, 1H), 2.22 (m, 1H), 2.03(m, 1H) and 1.78 (m, 2H).

Example 7: Methyl (4S)-4-(tritylamino)cyclopent-1-ene-1-carboxylate

A reactor was charged with a solution of methyl(1S,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylate (4.75 kg, 12.4 mol)in methylene chloride. The reactor was charged with additional methylenechloride (15 L) to bring the total volume to 23.8 L. To the stirredsolution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.82 L, 32.2mol). The reaction mixture was warmed to 40° C., with stirring for 16 to22 h. ¹H NMR (CDCl₃) analysis of a small sample of the reaction mixtureconfirmed the formation of the product. The reaction was washed with 10%aqueous citric acid solution (2×7 L). The organic phase was concentratedunder reduced pressure to afford the title compound as an oil. The oilwas diluted with anhydrous toluene and concentrated to remove residualwater and used without further purification. ¹H NMR (300 MHz, CDCl₃, δ):7.60-7.54 (m, 5H), 7.34-7.17 (m, 10H), 6.53-6.50 (m, 1H), 3.70 (s, 3H),3.50-3.40 (m, 1H), 2.60-2.52 (dd, J=16.6, 8.3 Hz, 1H), 2.24-2.20 (m,1H), 2.16-2.05 (m, 1H) and 1.91-1.80 (m, 1H).

Example 8: [(4S)-4-(tritylamino)cyclopent-1-en-1-yl]methanol

A reactor was charged with methyl(4S)-4-(tritylamino)cyclopent-1-ene-1-carboxylate (4.75 kg, 12.4 mol).The reactor was charged with anhydrous toluene (9.5 L), cooled to −5 to−10° C. and the agitation started. While maintaining the temperaturebetween −10° C. and +10° C., diisobutylaluminum hydride (1M solution intoluene, 23.4 kg, 27.3 mol) was added. Upon completion of the addition,the reaction mixture was analyzed by HPLC, which confirmed a completeconversion of the starting material to the product. The reaction mixturewas quenched into cold 2 N NaOH solution (−5 to −10° C.) at a rate tokeep the internal temperature below 20° C. The organic phase wasseparated and filtered through a pad of diatomaceous earth. The pad waswashed with toluene (2×1 L), and the filtrate was concentrated underreduced pressure to afford the title compound as a thick oil (5.15 kg).The product was diluted with methylene chloride and stored as a solutionat 0 to 5° C. ¹H NMR (300 MHz, CDCl₃, δ): 7.60-7.56 (m, 5H), 7.35-7.17(m, 10H), 5.38 (bs, 1H), 4.03-4.02 (d, J=3.7 Hz, 2H), 3.49-3.36 (m, 1H),2.40 (s, 2H), 2.19-1.79 (m, 4H), 1.32-1.29 (t, J=5.8 Hz, 1H).

Example 9:[(1S,3S,5S)-3-(tritylamino)-6-oxabicyclo[3.1.0]hex-1-yl]methanol

A reactor was charged with (+)-diethyl-L-tartrate (2.23 L, 13.0 mol) andmethylene chloride (10.5 L). Stirring was started and the mixture wascooled to −30 to −40° C. Titanium (IV) isopropoxide (3.93 L, 13.4 mol)was slowly added while maintaining the internal temperature between −30to −40° C. A solution of[(4S)-4-(tritylamino)cyclopent-1-en-1-yl]methanol (4.2 kg, 11.8 mol) inmethylene chloride (19 L) was slowly added to the reaction mixture,while maintaining the temperature between −30 to −40° C. After stirringfor 20 minutes, t-butyl hydroperoxide (5-6 M in decane, 3.3 L, 16.3 mol)was slowly added while maintaining the temperature between −30 to −40°C. Upon completion of the addition, the reaction mixture was analyzed byHPLC, which confirmed the formation of the product and presence of 3%(AUC) of the starting material. The reaction mixture was carefullyquenched into a 100-L reactor containing a cold aqueous solution (0 to5° C.) of iron (II) sulfate heptahydrate (10.5 kg) and tartaric acid(6.3 kg) in DI water (42 L). After stirring for 15 minutes, the organicphase was separated and filtered through a pad of diatomaceous earth.The pad was washed with methylene chloride (2×2 L), and the filtrate wastransferred into a 100-L reactor. A cold solution (0 to 5° C.) of solidsodium hydroxide (3.36 kg) in brine (42 L) was slowly added to thegently stirred reaction mixture. After 1 h, the organic phase wasseparated, dried over anhydrous sodium sulfate, filtered through a padof diatomaceous earth and concentrated under reduced pressure to give abrown oil. This was purified via silica-gel chromatography using fivecolumns. Each column was performed as follows. A 20 cm diameter glasscolumn was loaded with a slurry of silica gel (5 kg) in 30% ethylacetate/heptane with 0.5% triethylamine added. Crude product (˜1.2 kg)was adsorbed onto silica gel (1.5 kg) and loaded on the column. Polaritywas gradually increased from 30% to 40% ethyl acetate/heptane with 0.5%triethylamine. Combined purified material from all columns afforded thetitle compound (3.93 kg, 89% yield) as an amber oil. ¹H NMR (300 MHz,CDCl₃, δ) 7.54-7.50 (m, 5H), 7.32-7.18 (m, 10H), 3.80-3.76 (d, J=12.5Hz, 1H), 3.65-3.61 (d, J=12.5 Hz, 1H), 3.31 (s, 1H), 3.03-2.92 (m, 1H),1.77-1.69 (m, 2H) and 1.37-1.13 (m, 2H).

Example 10: (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanoland (1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol

A reactor was charged with a methylene chloride solution of[(1S,3S,5S)-3-(tritylamino)-6-oxabicyclo[3.1.0]hex-1-yl]methanol (2.76kg, 7.4 mol). The reactor was charged with additional methylene chloride(5 L) to bring the total to 13.8 L. The stirred reaction mixture washeated to 35° C. to 40° C. Using a solid addition system, sodiumborohydride (281 g, 7.4 mol) was added portion wise while maintainingthe temperature between 35° C. and 45° C. Borane-THF complex (1 Msolution in THF, 6.7 kg, 7.4 mol) was slowly added while maintaining thetemperature between 35 to 45° C. The temperature was maintained at 35 to40° C. for 1 hour, and then the reaction mixture was analyzed by HPLC.The reaction was deemed complete when the amount of starting materialwas less than 2%. The reaction mixture was cooled to less than 30° C.,then carefully quenched into a 100-L reactor containing cold DI water(28 L). After stirring for 3 hours, the organic phase was separated anddried over anhydrous magnesium sulfate, filtered through a pad ofdiatomaceous earth and concentrated under reduced pressure to afford amixture of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol and(1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (2.74 kg) as abrown oil, which was used without further purification.

Example 11:(1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol

A reactor was charged with the mixture of(1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol and(1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (1.87 kg total,˜280 g of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol,0.75 mol). The reactor was charged with methylene chloride (7.4 L) andthe agitation started. While maintaining the temperature less than 25°C., triethylamine (210 mL, 1.5 mol) was added. While maintaining thetemperature less than 25° C., triisopropylsilyl chloride (402 mL, 1.9mol) was slowly added. The reaction mixture was allowed to stir at 20°C. to 22° C., for ˜48 hours. The reaction mixture was analyzed by TLC(50% ethyl acetate/heptane, UV visualization), which indicated theformation of the product (R_(f)0.70) and the presence of unreacted(1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (R_(f)0.15). Theclear pale yellow solution was cooled to 5 to 10° C., slowly quenchedwith DI water (7.5 L), and the resulting layers separated. The aqueousphase was extracted with methylene chloride (3 L) and the combinedorganic phases were dried over anhydrous magnesium sulfate, filteredthrough a pad of diatomaceous earth and concentrated under reducedpressure to give a brown oil (4.06 kg), which was purified by silica gelchromatography using multiple columns. Each column was performed asfollows. A 20 cm diameter glass column was loaded with a slurry ofsilica gel (4.5 kg) in 10% ethyl acetate/heptane. The oil (˜1.2 kg) wasloaded on the column. Combined purified material from all columnsafforded the title compound (2.94 kg) as a clear oil which was usedwithout further purification. ¹H NMR (300 MHz, CDCl₃, δ): 7.56-7.54 (m,5H), 7.34-7.13 (m, 10H), 4.26 (bs, 1H), 3.86-3.81 (dd, J=10.0, 4.5 Hz,1H), 3.65-3.60 (dd, J=10.1, 7.2 Hz, 1H), 3.41-3.37 (m, 1H), 3.07 (bs,1H), 2.16-2.07 (m, 1H), 1.69-1.63 (m, 3H), 1.47-1.20 (m, 4H) and1.08-1.03 (2 s, 18H).

Example 12: (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol

A reactor was charged with(1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol(2.94 kg total, ˜1.6 kg assumed pure material, 3.02 mol,). The reactorwas charged with THF (6 L) and agitation started. While maintaining thetemperature less than 25° C., tetrabutylammonium fluoride (1M solutionin THF, 3.02 L, 3.0 mol) was added. The reaction mixture was allowed tostir at 20° C. to 22° C., for 3 hours. TLC (50% ethyl acetate/heptane,UV visualization) confirmed a complete conversion of the startingmaterial to the product. The reaction mixture was concentrated underreduced pressure to ˜2 L volume and transferred to a second reactor. Theconcentrate was diluted with methylene chloride (16 L), washed withsaturated aqueous ammonium chloride (8 L), and DI water (8 L). Theorganic phase was dried over anhydrous magnesium sulfate, filteredthrough a pad of diatomaceous earth and concentrated under reducedpressure to give an amber oil (3.88 kg) which was purified by silica gelchromatography. Two columns were performed as follows. A 20 cm diameterglass column was loaded with a slurry of silica gel (5 kg) in 10% ethylacetate/heptane. About 1.9 kg of the oil was adsorbed onto silica gel(1.5 kg) and loaded on the column and the polarity was graduallyincreased from 10% to 50% ethyl acetate/heptane. Pure fractions werecombined and concentrated under reduced pressure to afford the titlecompound (800 g) as a white solid. ¹H NMR (300 MHz, CDCl₃, δ): 7.57-7.53(m, 5H), 7.32-7.18 (m, 10H), 4.26-4.23 (m, 1H), 3.65-3.46 (m, 2H),3.36-3.29 (m, 1H), 2.17-2.07 (m, 2H), 1.65-1.62 (d, 1H), 1.51-1.39 (m,2H), 1.37-1.26 (m, 1H) and 1.2-1.17-1.11 (m, 1H).

Example 13: (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol

A hydrogenation reactor was purged with argon and charged with 5%palladium on carbon (50% water wet, 80 g, 20 mol %) and the reactorsealed. Using vacuum, a solution of(1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol (400 g, 1.07mol) in methanol (2.7 L) was added to the reactor. The reactor waspurged with argon, charged to 35 to 45 psi hydrogen and heated to 35° C.for 72 h. The reaction mixture was filtered through a pad ofdiatomaceous earth, washed with methanol (32 L) and concentrated underreduced pressure to ˜1 L volume. Precipitated triphenyl methane wasfiltered from the mixture and the filtrate further concentrated to givean amber oil. The crude material was purified by silica-gelchromatography. The column was performed as follows. A 15 cm diameterglass column was loaded with a slurry of silica gel (1.6 kg) inmethylene chloride. The amber oil was adsorbed onto silica gel (200 g)and loaded on the column. The polarity was gradually increased from 100%methylene chloride to 50% methylene chloride/methanol. The purefractions were combined and concentrated under reduced pressure toafford the title compound (118 g) as a waxy yellow solid. ¹H NMR (300MHz, CD₃OD, δ): 4.35-4.32 (m, 1H), 3.76-3.70 (m, 1H), 3.64-3.56 (m, 2H),2.34-2.26 (m, 1H), 2.10-2.03 (m, 1H), 1.93-1.82 (m, 1H) and 1.63-1.46(m, 2H).

Example 14:(1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

To a slurry of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (10.0 g,0.0377 mol) and (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol.HBr(8.00 g) in isopropyl alcohol (82 mL, 1.1 mol) and water (11 mL, 0.59mol), triethylamine (13 mL, 0.094 mol) was added. This mixture was thenheated to 85° C. for 23 hours. The mixture was cooled to 50° C., atwhich point 4M hydrochloric acid in water (20 mL) was added slowly. Theresulting mixture was then stirred at 50° C. for 3 hours. HPLC indicatedthat the reaction was complete. The reaction mixture was cooled toambient temperature and sodium bicarbonate (10 g, 0.1 mol) was addedportionwise. Excess solids were filtered; the bed washed with isopropylalcohol (20 mL) and the filtrate concentrated to ˜70 mL. Ethyl acetate(150 mL) was added followed by a mixture of saturated NaHCO₃ aq (35 mL)and water (35 mL). The layers were separated and the aqueous phasesextracted with ethyl acetate (2×50 mL) and filtered. The organic layerswere combined and washed with saturated NaCl aq (50 mL) and thenconcentrated to afford the title compound (9.3 g) as a brown solid. ¹HNMR (300 MHz, CD₃OD, δ): 8.56 (s, 1H), 7.67 (d, 1H), 6.65 (d, 1H), 5.52(m, 1H), 4.50 (m, 1H), 3.79 (m, 1H), 3.66 (m, 1H), 2.63 (m, 1H), 2.25(m, 3H) and 2.02 (m, 1H).

Example 15:(1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

A solution of (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (250 mg,1.90 mmol) and triethylamine (380 mg, 3.80 mmol) in 2-propanol (30 mL)was treated with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (330 mg,1.71 mmol) at 80° C. The reaction was monitored by HPLC and all aldehydewas found to have been consumed after 19 h. The reaction mixture wascooled to ambient temperature. Approximately 80% of the solvent wasremoved under reduced pressure and the resulting brown solution wasadded with stirring to water (30 mL). The resulting clear solution wascooled in an ice-water bath resulting in product crystallization. Theresulting slurry was stirred at less than 5° C. for thirty minutes andfiltered. The filter cake was washed with cold water (10 mL) and driedin a vacuum oven at 40° C. for 14 h to obtain the title compound as abrown solid (311 mg, 68% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.54 (s, 1H),7.68 (d, J=3.7 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 5.54 (m, 1H), 4.52 (m,1H), 3.82 (dd, J=10.7, 7.2 Hz, 1H), 3.68 (dd, J=10.8, 6.5 Hz, 1H), 2.64(m, 1H), 2.32 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H).

Example 16: 9-phenylheptadecan-9-ol

Methyl benzoate (14.34 g, 105.3 mmol) was dissolved in anhydrous THF (43mL) and this mixture was cooled to 0° C. A solution ofn-octylmagnesiumchloride in THF (200.0 mL, 2.0M, 400 mmol) was thenadded dropwise, keeping the temperature at less than 10° C. Uponcompletion of addition, the mixture was left to stir at 0° C. for 2hours. A solution of hydrochloric acid in water (400 mL, 1.0 M) was thenadded dropwise keeping the temperature at less than 25° C. The mixturewas diluted with iPrOAc (420 mL) and the resulting organic layer waswashed with 1.0 M HCl (1×70 mL), washed with brine (1×70 mL), dried oversodium sulfate and evaporated to yield a colorless liquid. The crudematerial was purified by silica gel column chromatography to afford aclear colorless liquid (21.0 g). ¹H NMR (300 MHz, CDCl₃, δ): 7.41-7.30(m, 4H), 7.28-7.20 (m, 1H), 1.90-1.70 (m, 4H), 1.35-1.20 (m, 23H),1.11-0.96 (m, 2H) and 0.92-0.83 (m, 6H).

Example 17: 1-octyl-1-phenylnonyl (chlorosulfonyl)carbamate

Chlorosulfonyl isocyanate (1.30 mL, 14.95 mmol) was dissolved inanhydrous THF (10 mL) and this mixture was cooled to 0° C. A solution of9-phenylheptadecan-9-ol (4.972 g, 14.95 mmol) in anhydrous THF (18.5 mL)was added dropwise keeping the temperature at less than 10° C. Uponcompletion of addition, the mixture was left to stir at 0° C. for 1hour. The resulting approximately 0.5 M solution of1-octyl-1-phenylnonyl (chlorosulfonyl)carbamate was stored at 0° C.until use.

Example 18: General preparation of 4-amino substituted(1S,2S,4R)-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanols

(1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol(1 equiv.), an amine as listed in Table 1 below (1.1 equiv.) andN,N′-diisopropylethylamine (1.3 equiv.) are mixed in 2-butanol(approximately 6 volumes). The reaction vessel is purged with nitrogenand then is heated under pressure (80 psi) at 135° C. for about 40 hoursor until HPLC indicates little or no remaining starting material. Themixture is cooled to ambient temperature and pressure. Ethyl acetate isadded to the reaction mixture and the organic layer is separated andwashed with water. The aqueous layer is separated and washed with ethylacetate. The combined organic layers are washed with saturated NaClsolution and dried over Na₂SO₄, filtered and concentrated. Methylenechloride is added to the mixture which is cooled to 0° C. for about onehour. The resulting solid is filtered and washed with cold methylenechloride. The solid is dried under vacuum at ambient temperature.

TABLE 1 Suitable amines for use in Example 18

amine-i

amine-ii

amine-iii

amine-iv

amine-v

amine-vi

amine-vii

amine-viii

amine-ix

amine-x

amine-xi

amine-xii

amine-xiii

amine-xiv

amine-xv

amine-xvi

amine-xvii

Example 19: General Sulfamoylating Conditions 1

To a reaction vessel is added triethylenediamine (approximately 4 equiv.with respect to input product of Example 18) and tetrahydrofuran(approximately 12 volumes with respect to input product of Example 18).The mixture is cooled to 0° C. and 0.866 M of tert-butyl(chlorosulfonyl)carbamate (prepared by adding tert butyl alcohol to amolar equivalent of chlorosulfonyl isocyanate in the appropriate amountof anhydrous THF and stirring for about 1 hour whilst keeping thetemperature below about 15° C.) in tetrahydrofuran (approximately 3equiv. with respect to input product of Example 18) is added withcooling at such a rate that the internal temperature remains less thanor equal to 15° C. The suspension is warmed to ambient temperature andstirred for about 30 minutes, then cooled to −20° C. The product fromExample 18 is added in one portion followed by additionaltetrahydrofuran (approximately 3 volumes with respect to input productof Example 18). The reaction mixture is warmed to 0° C. and allowed tostir until HPLC indicates that there is less than 1% by area startingmaterial present. The reaction mixture is cooled to 0° C. and 9Mhydrochloric acid in water (approximately 25 volumes with respect toinput product of Example 18) is added slowly maintaining a temperatureof less than 25° C. The resulting mixture is then allowed to warm toambient temperature and stirred for about 4 hours or until such time asHPLC indicates complete BOC deprotection. On completion of deprotection,sodium bicarbonate is added portionwise until pH˜8 is reached. Excesssolids are filtered if a biphasic mixture is observed and the bed iswashed with ethyl acetate. The organic layer is separated. The aqueouslayer is extracted with ethyl acetate, all the organics are combined andwashed with saturated NaCl aq., and concentrated to give a crude productwhich is purified by column chromatography. The product can be furtherpurified by crystallization from an appropriate solvent.

Example 20. General Sulfamoylating Reagent Preparation 1

To a reaction vessel is added the alcohol of formula (R^(w))(R^(v))₂C—OH(1.1 equiv) and anhydrous methylene chloride (approximately 20 volumes)and the mixture is cooled to about 0° C. to 10° C. Chlorosulfonylisocyanate (1 equiv) is added at a rate that keeps the temperature belowabout 10° C. and the mixture is stirred for about 1 hour. A base (2.6equiv.) is added portionwise whilst keeping the temperature below about15° C. and the mixture is then stirred for about 1 hour at about 0° C.to 15° C. The solids are removed by filtration and the bed is washedwith methylene chloride (approximately 5 volumes). The solvent isremoved under reduced pressure and acetonitrile (approximately 5volumes) is added to the residue and the resultant suspension is stirredat room temperature for about 3 hours. The sulfamoylating reagent iscollected by filtration, washed with acetonitrile (1 volume) and driedunder vacuum.

Example 21: General Sulfamoylating Conditions 2

To a reaction vessel is added the product from Example 18 (1 equiv.) andNMP (approximately 9 volumes with respect to the input product fromExample 18). The mixture is cooled to between about 0° C. to 10° C. andstirred for about 15 minutes. The sulfamoylating reagent generated inExample 20 (1 equiv. with respect to input product from Example 18) andan acid (1 equiv. with respect to the input product from Example 18) isadded and the mixture is stirred at a temperature of between about 0° C.to 10° C. The reaction is followed by HPLC. A further 1 equivalentportion of the sulfamoylating reagent generated in Example 20 and theacid are added approximately hourly until the reaction is complete.Water (approximately 2.5 volumes with respect to the input product fromExample 18) is added and the mixture is stirred at about 15° C. forabout 16 hours. Ethyl acetate (approximately 15 volumes with respect tothe input product from Example 18) and water (10 volumes with respect tothe input product from Example 18) are added, the resulting mixture isstirred for about 10 minutes and the resulting layers are separated. Theorganic phase is then washed with water (3×15 volumes with respect tothe input product from Example 18). The organic phase is then dried overanhydrous sodium sulfate and the solvent is removed under reducedpressure.

The crude product is dried under vacuum before redissolving inacetonitrile (6.5 volumes with respect to the input product from Example18). Hydrochloric acid (2.4 volumes with respect to the input productfrom Example 18) is added while keeping the reaction temperature belowabout 20° C. The reaction is followed by HPLC until removal of theprotecting group is complete. Water (approximately 14 volumes withrespect to the input product from Example 18) is added followed bysodium bicarbonate until a pH of 7-8 is achieved. Ethyl acetate(approximately 15 volumes with respect to the input product from Example18) is added and after stirring for about 10 minutes the layers areseparated. The organic layer is washed with water (approximately 3×15volumes with respect to the input from Example 18) and is dried overanhydrous sodium sulfate. The solvent is removed and the residuedissolved in 7% acetonitrile in methylene chloride (approximately 11volumes with respect to the input product from Example 18) and isstirred for about 18 hours. The product is harvested by filtration anddried under vacuum at between 30° C.−35° C.

Example 22: General Sulfamoylating Reagent Preparation 2

To a reaction vessel is added chlorosulfonyl isocyanate (1 equiv) andanhydrous toluene (approximately 20 volumes), and the mixture is cooledto about 0-10° C. Tert-butyl alcohol (1 equiv) is added at a rate tokeep the reaction temperature below about 10° C., and the mixture isstirred for about 1 hour. Triethylenediamine (2 equiv.) is addedportionwise whilst keeping the temperature below about 15° C., and themixture is then stirred for about two hours at a temperature betweenabout 15° C. to about 25° C. The sulfamoylating reagent is collected byfiltration under nitrogen protection and dried under vacuum.

Example 23: General Sulfamoylating Conditions 3

To a reaction vessel is added the product from Example 18 (1 equiv.) andacetonitrile (approximately 7 volumes with respect to the input productfrom Example 18). The sulfamoylating reagent generated in Example 22 (2equiv. with respect to input product from Example 18) is added and themixture is stirred at a temperature of about 50° C. The reaction isfollowed by HPLC. Heating is allowed to continue until the reaction iscomplete. After cooling to room temperature, 0.5 N HCl (approximately5.5 volumes with respect to the input product from Example 18) is addedand the mixture is stirred at about 23° C. for about 5-6 hours. Theaqueous phase is separated from the resulting biphasic solution andextracted with MTBE (approximately 5 volumes with respect to the inputproduct from Example 18). The MTBE extract is combined with previouslyseparated organic phase and additional MTBE (about 2 volumes withrespect to the input product from Example 18) is added. The resultingmixture is stirred with water (approximately 10 volumes with respect tothe input product from Example 18) for 10 minutes. The organic phase isseparated. To the organic phase is added acetonitrile (approximately 10volumes with respect to the input product from Example 18), and thesolution is reduced to 10 volumes with respect to the input of productfrom Example 18 under reduced pressure. Additional acetonitrile(approximately 8 volumes with respect to the input of product fromExample 18) is added, and again the solution is reduced to 10 volumeswith respect to the input of product from Example 18 under reducedpressure.

To the crude product acetonitrile solution is added slowly, concentratedhydrochloric acid (3 volumes with respect to the input product fromExample 18) while keeping the reaction temperature below about 5° C. Thereaction is followed by HPLC until removal of the protecting group iscomplete. Water (approximately 10 volumes with respect to the inputproduct from Example 18) is added followed by sodium bicarbonate until apH of 7-8 is achieved. Ethyl acetate (approximately 10 volumes withrespect to the input product from Example 18) is added and afterstirring for about 10 minutes the layers are separated. The organiclayer is washed with water (approximately 3×10 volumes with respect tothe input from Example 18). Brine (about 5% v/v) is optionally addedduring the 2^(nd) and 3^(rd) washes to help phase separation. The crudeproduct solution is optionally allowed to pass through a plug ofactivated carbon or silica gel (about 250%-25% w/w with respect to theinput product from Example 18). EtOAc (about 2-10 volumes with respectto the input product from Example 18) is used to flush the activatedcarbon or silica gel plug. The resulting solution is concentrated toapproximately 3 volumes with respect to the input product from Example18, and then heated at 35-40° C. Dichloromethane (20 volumes withrespect to the input product from Example 18) is added slowly while theinternal temperature is kept at 35-40° C. After addition of DCM iscomplete, the suspension is stirred at 35-40° C. for 1 hour, and allowedto cool to room temperature and then stirred at room temperature forabout 18 hours. The resulting solid is collected by filtration and driedunder vacuum at 30-35° C. to a constant weight.

Example 24: Tert-butyl[(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo[3.2.0]hept-3-yl]carbamate

To (1R,4R)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylicacid (400.00 g, 1.7601 mol; prepared in a procedure analogous to thatdescribed in Examples 1 to 3 above) dissolved in methylene chloride (6L) was added tetrabutylammonium hydroxide in methanol (1.0M, 1800 ml),and the mixture was stirred at ambient temperature for 60 minutes. Thereaction mixture was then cooled to −25° C. under a blanket of Nitrogen.Bromine (181 ml, 3.52 mol) in methylene chloride (2 L) was then addedslowly over 60 minutes, maintaining an internal temperature lower than−20° C. On completion of the bromine addition, the mixture was stirredat −25° C. for a further 30 minutes, and then warmed slowly to 0° C.over 30 minutes. The mixture was then allowed to stir at 0° C. for 1hour. At 0° C., a mixture of L-ascorbic acid sodium salt (523.0 g, 2.640mol) in water (3 L) and saturated sodium bicarbonate in water (3 L), wasadded slowly over 30 minutes maintaining an internal temperature lowerthan 10° C. The resulting bi-phasic mixture was stirred and allowed towarm to ambient temperature over 1 hr. The methylene chloride layer wasseparated and the aqueous layer was extracted with methylene chloride (2L). The methylene chloride layers were combined and concentrated to avolume of about 4 L. Ethyl acetate (8 L) was added, and the mixture wasconcentrated to a volume of about 5 L. Ethyl acetate (5 L) was added,and the resulting mixture was washed 3 times with water (4 L). Theorganic layer was then washed with saturated sodium chloride in water (2L) and concentrated to afford the title compound (460 g, 85%) as a whitesolid. ¹H NMR (300 MHz, CDCl3): δ 5.09 (d, 1H), 4.80 (m, 1H), 4.71 (m,1H), 4.47 (m, 1H), 4.04 (m, 1H), 2.39 (m, 1H), 1.89 (m, 1H) and 1.46(bs, 9H).

Example 25: Tert-butyl[(1R,2R,3R,4S)-2-bromo-3-hydroxy-4-(hydroxymethyl)cyclopentyl]carbamate

Tert-butyl[(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo[3.2.0]hept-3-yl]carbamate(450.0 g, 1.470 mol) was dissolved in THF (6 L) and the mixture wascooled to 0° C. 2.0M lithium tetrahydroborate in THF (730 ml) was addedslowly, maintaining an internal temperature lower than 10 OC. Themixture was then stirred at 0° C. for 30 minutes, after which HPLCindicated that the starting material had been consumed. At 0° C., amixture of saturated ammonium chloride in water (2.5 L) and water (2.5L) was added slowly, maintaining an internal temperature lower than 10°C. The mixture was then allowed to warm to ambient temperature, at whichpoint the THF layer was separated. The THF layer was concentrated toabout 2 L, and the aqueous layer was extracted twice with ethyl acetate(4 L). The organic layers were combined and washed twice with water (4L). The organic layer was then washed with saturated sodium chloride inwater (4 L) and concentrated to yield the title compound (452 g, 99%) asa yellow residue. ¹H NMR (300 MHz, CDCl3): δ 4.83 (m, 1H), 4.54 (m, 1H),4.43 (m, 1H), 4.31 (m, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 2.71 (m, 1H),2.02 (m, 1H), 1.70 (m, 1H) and 1.41 (bs, 9H).

Example 26: (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol.HBr

Tert-butyl[(1R,2R,3R,4S)-2-bromo-3-hydroxy-4-(hydroxymethyl)cyclopentyl]carbamate(444.0 g, 1.431 mol) was dissolved in isopropyl alcohol (2000 ml). Tothis solution, 4.0M hydrochloric acid in 1,4-dioxane (2000 ml) was addedand the mixture was stirred at ambient temperature for 3 hours. Analiquot was concentrated and analyzed by ¹H NMR, which indicated thatthe starting material had been consumed. The remaining reaction mixturewas concentrated under reduced pressure at 35° C. to give a clearresidue. This residue was dissolved in a mixture of methanol (2000 ml)and isopropyl alcohol (2000 ml), to which 10 weight % Pd/C (76 g, 2.5mol %) followed by sodium bicarbonate (360 g, 4.3 mol) was added. Theresulting heterogeneous mixture was subjected to hydrogen (20 psi) atambient temperature for 18 hours. An aliquot of the reaction mixture wassyringe filtered, concentrated, and analysis by ¹H NMR indicated thecomplete consumption of the starting material. The remaining reactionmixture was filtered through a pad of Celite (250 g). The filter bed waswashed with methanol (2000 ml) and the filtrate concentrated underreduced pressure at 35° C., to yield the title compound (310 g,quantitative) as an orange solid. ¹H NMR (300 MHz, CD3OD): δ4.17 (t,1H), 3.83 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 2.33 (m, 1H), 2.21 (m,1H), 2.03 (m, 1H) and 1.79 (m, 2H).

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, these particular embodiments areto be considered as illustrative and not restrictive. It will beappreciated by one skilled in the art from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention, which is to be defined by theappended claims rather than by the specific embodiments.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

What is claimed is:
 1. A compound of formula (Ia):

or a salt thereof; wherein: stereochemical configurations depicted atasterisk positions indicate absolute stereochemistry; R^(a) is hydrogen;or R^(a) taken together with R^(j) and the intervening atoms forms acyclic diol protecting group; R^(b) is hydrogen; R^(c) is hydrogen;R^(d) is hydrogen; R^(e) is hydrogen; R^(e′) is hydrogen; each R^(f) isindependently hydrogen; R^(g′) is chloro, bromo, fluoro, or iodo; R^(h)is hydrogen; R^(h′) is hydrogen; R^(j) is hydrogen; or R^(j) takentogether with R^(a) and the intervening atoms forms a cyclic diolprotecting group; R^(k) is hydrogen.
 2. The compound of claim 1, whereinthe compound is:


3. The compound of claim 1, wherein each of R^(a) and R^(j) is hydrogen.4. The compound of claim 3, wherein R^(g′) is chloro, bromo, or iodo. 5.The compound of claim 4, wherein R^(g′) is chloro or bromo.
 6. Thecompound of claim 1, wherein R^(g′) is chloro, bromo, fluoro, or iodo.7. The compound of claim 6, wherein R^(g′) is chloro or bromo.